Impact Factor 6.429

The 5th most cited journal in Immunology

Classification ARTICLE

Front. Immunol., 20 November 2015 | https://doi.org/10.3389/fimmu.2015.00588

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death

imageAbhishek D. Garg1*, imageLorenzo Galluzzi2,3,4,5,6, imageLionel Apetoh7,8,9, imageThais Baert10,11, imageRaymond B. Birge12, imageJosé Manuel Bravo-San Pedro2,3,4,5,6, imageKarine Breckpot13, imageDavid Brough14, imageRicardo Chaurio15, imageMara Cirone16, imageAn Coosemans10,11, imagePierre G. Coulie17, imageDirk De Ruysscher18, imageLuciana Dini19, imagePeter de Witte20, imageAleksandra M. Dudek-Peric1, imageAlberto Faggioni21, imageJitka Fucikova22,23, imageUdo S. Gaipl24, imageJakub Golab25, imageMarie-Lise Gougeon26, imageMichael R. Hamblin27, imageAkseli Hemminki28,29,30, imageMartin Herrmann15, imageJames W. Hodge31, imageOliver Kepp2,3,4,5,32, imageGuido Kroemer2,3,4,5,32,33,34, imageDmitri V. Krysko35,36, imageWalter G. Land37, imageFrank Madeo38,39, imageAngelo A. Manfredi40, imageStephen R. Mattarollo41, imageChristian Maueroder15, imageNicolò Merendino42, imageGabriele Multhoff43, imageThomas Pabst44, imageJean-Ehrland Ricci45, imageChiara Riganti46, imageErminia Romano1, imageNicole Rufo1, imageMark J. Smyth47,48, imageJürgen Sonnemann49, imageRadek Spisek22,23, imageJohn Stagg50, imageErika Vacchelli2,3,4,5,6, imagePeter Vandenabeele35,36, imageLien Vandenberk51, imageBenoit J. Van den Eynde52, imageStefaan Van Gool51, imageFrancesca Velotti53, imageLaurence Zitvogel6,54,55,56 and imagePatrizia Agostinis1*
  • 1Cell Death Research and Therapy Laboratory, Department of Cellular Molecular Medicine, KU Leuven – University of Leuven, Leuven, Belgium
  • 2Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
  • 3U1138, INSERM, Paris, France
  • 4Université Paris Descartes, Sorbonne Paris Cité, Paris, France
  • 5Université Pierre et Marie Curie, Paris, France
  • 6Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
  • 7U866, INSERM, Dijon, France
  • 8Faculté de Médecine, Université de Bourgogne, Dijon, France
  • 9Centre Georges François Leclerc, Dijon, France
  • 10Department of Gynaecology and Obstetrics, UZ Leuven, Leuven, Belgium
  • 11Laboratory of Gynaecologic Oncology, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
  • 12Department of Microbiology, Biochemistry, and Molecular Genetics, University Hospital Cancer Center, Rutgers Cancer Institute of New Jersey, New Jersey Medical School, Newark, NJ, USA
  • 13Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Jette, Belgium
  • 14Faculty of Life Sciences, University of Manchester, Manchester, UK
  • 15Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nurnberg, Erlangen, Germany
  • 16Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
  • 17de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
  • 18Department of Radiation Oncology, University Hospitals Leuven, KU Leuven – University of Leuven, Leuven, Belgium
  • 19Department of Biological and Environmental Science and Technology, University of Salento, Salento, Italy
  • 20Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven – University of Leuven, Leuven, Belgium
  • 21Sapienza University of Rome, Rome, Italy
  • 22SOTIO, Prague, Czech Republic
  • 23Department of Immunology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic
  • 24Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany
  • 25Department of Immunology, Medical University of Warsaw, Warsaw, Poland
  • 26Biotherapy and Vaccine Unit, Institut Pasteur, Paris, France
  • 27Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
  • 28Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
  • 29Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
  • 30TILT Biotherapeutics Ltd., Helsinki, Finland
  • 31Recombinant Vaccine Group, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  • 32Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
  • 33Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
  • 34Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden
  • 35Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, Ghent, Belgium
  • 36Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
  • 37Molecular ImmunoRheumatology, INSERM UMRS1109, Laboratory of Excellence Transplantex, University of Strasbourg, Strasbourg, France
  • 38Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
  • 39BioTechMed Graz, Graz, Austria
  • 40IRRCS Istituto Scientifico San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy
  • 41Translational Research Institute, University of Queensland Diamantina Institute, University of Queensland, Wooloongabba, QLD, Australia
  • 42Laboratory of Cellular and Molecular Nutrition, Department of Ecological and Biological Sciences, Tuscia University, Viterbo, Italy
  • 43Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  • 44Department of Medical Oncology, University Hospital, Bern, Switzerland
  • 45INSERM, U1065, Université de Nice-Sophia-Antipolis, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe “Contrôle Métabolique des Morts Cellulaires”, Nice, France
  • 46Department of Oncology, University of Turin, Turin, Italy
  • 47Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Insitute, Herston, QLD, Australia
  • 48School of Medicine, University of Queensland, Herston, QLD, Australia
  • 49Department of Paediatric Haematology and Oncology, Children’s Clinic, Jena University Hospital, Jena, Germany
  • 50Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Institut du Cancer de Montréal, Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada
  • 51Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven – University of Leuven, Leuven, Belgium
  • 52Ludwig Institute for Cancer Research, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
  • 53Department of Ecological and Biological Sciences, Tuscia University, Viterbo, Italy
  • 54University of Paris Sud, Le Kremlin-Bicêtre, France
  • 55U1015, INSERM, Villejuif, France
  • 56Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called “damage-associated molecular patterns” (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Introduction and Historical Background

Augmenting the immunogenicity of cancer cells to improve the efficacy of cancer therapy is a paradigm that has gained significant momentum over the past 5 years (15). Researchers have realized that besides therapeutically exploiting innate or adaptive immune cells directly (e.g., through dendritic cell (DC)-based vaccines or adoptive T-cell transfer) and/or improving the effector functions of T cells (through checkpoint-blocking therapies), cancer cells also need to be made immunogenic (1, 4, 6, 7). This has diverted attention toward studying the interface between stressed or dying cancer cells and the immune system, in the hope of efficiently exploiting it for therapeutic purposes (1).

Early indications regarding immune system-driven tumor control emerged in the eighteenth century, when feverish infections in cancer patients were circumstantially associated with tumor remission (8). The first evidence that immunotherapy can be applied to achieve tumor regression emerged from the work of William Coley, who in the 1890s achieved tumor regression in some sarcoma/lymphoma patients upon the intra-tumoral injection of streptococcal cultures (provided by Robert Koch) (8, 9). In the following 43 years, Coley injected nearly 900 (mostly sarcoma) patients with his bacterial preparation (achieving a cure rate >10%), which later became known as “Coley’s toxin” (8, 10). However, the Coley’s toxin came under intense scrutiny owing to an elevated toxicity and some difficulties in reproducing remission rates (8). Eventually, the first experimental evidence that virus-unrelated tumors can indeed be recognized by the host immune system emerged in the 1940s, and by the 1960s, coupled with the discovery of T cells, it was proposed that the human immune system may also react against tumors (11). The ability of anticancer therapies to enhance the immunogenic potential of malignant cells gained some appreciation by the 1970s (1214). It was recognized that if specific treatments are applied (e.g., radiotherapy, the bacillus Calmette–Guerin, or some chemotherapeutics), the immunogenicity of malignant cells increases enough to induce durable anti-tumor immunity (1214). By the 1980s, researchers started to report more specific observations regarding the therapeutic impact of cancer cell immunogenicity, e.g., the ability of curative hyperthermia to cause the (heat-shock based) generation of circumstantial anti-tumor immunity (15), the fact that the immunogenicity of cancer cells influences patient prognosis after radiotherapy (16), and the increase in tumor immunogenicity due to hydrostatic pressure (17). However, these early studies (especially those published before the 1980s) had several issues linked to a lack in consensus. For instance, due to early controversies on the existence of tumor-associated antigens (TAAs) (11), the target of tumor-specific immune responses was unclear, and the mechanism of action of some therapies came under scrutiny. Moreover, such therapies could operate by directly modulating immune effector cells rather than improving the immunogenic potential of tumors (18). In particular, the death of cancer cells exposed to therapy was never suspected to drive anti-tumor immunity, since it was considered to be a relatively “silent” process in terms of immunogenicity (19). Moreover, the classical “self/non-self” theory was unable to explain the possibility that dying cancer cells could elicit an immune response (20).

By the early 1990s, the molecular characterization of mice and human TAAs clarified the entities targeted by anti-tumor immune responses (11). Similarly, the so-called “danger theory” started to emerge, challenging the classical model of “self/non-self” immune recognition, especially in a diseased or damaged tissue (20, 21). This model proposed that the immune recognition is not restricted to “non-self” entities, but rather discriminates between “dangerous” and “safe” entities, irrespective of source (2022). Indeed, “dangerous” entities include pathogens as well as injured, infected, diseased and necrotic tissues, or cells undergoing non-physiological cell death which emit danger signals (or alarmins) with pro-inflammatory activity (21, 22). These danger signals are now collectively referred to as “damage-associated molecular patterns” (DAMPs) (23). DAMPs are endogenous molecules that are concealed intracellularly in normal conditions, but are exposed or released upon stress, injury, cell death, thereby becoming able to bind cognate receptors on immune cells (3, 2427). Table 1 summarizes the most prominent DAMPs characterized to date and their mode of emission, the cell death pathway they are associated with, and their known cognate receptors. It is important to consider that not all DAMPs may act as immunogenic danger signals. Several DAMPs exist that are crucial for the maintenance of tissue homeostasis, and the avoidance of auto-immune responses, as they exert immunosuppressive effects, including phosphatidylserine (PS), annexin A1 (ANXA1), death domain 1α (DD1α), B-cell CLL/lymphoma 2 (BCL2) and some extracellular matrix-derived molecules (Table 1). Accordingly, the blockade of these anti-inflammatory DAMPs accentuates the immunogenic potential of dying cells, or renders immunogenic otherwise tolerogenic forms of cell death (28, 29). Moreover, some danger signals are not always involved in the immunogenicity of cell death, but act as “bystanders.” This is the case for heat shock protein 90 kDa alpha (cytosolic), class A member 1 (HSP90AA1, best known as HSP90) exposed on the cell surface after melphalan treatment (30). Last (but not least), several DAMPs may be subjected to post-translational modifications (e.g., oxidation, reduction, citrullination) that may potentially neutralize, increase, or change their immunogenic properties (31, 32) – a process that is still incompletely understood.

TABLE 1
www.frontiersin.org

Table 1. A list of prominent damage-associated molecular patterns (DAMPs) associated with cell death pathways or extracellular matrix.

Despite these advances, the overall role of regulated cell death (RCD) (97) in augmenting cancer immunogenicity remained obscure. Initial observations involving the immunogenicity of cell death in the efficacy of cancer therapy were published between 1998 and 2004, when it was proposed that the non-apoptotic demise of malignant cells (within the context of the so-called “immunogenic death”) could be associated with the emission of the danger signal heat shock 70 kDa protein 1A (HSPA1A, best known as HSP70) (Table 1), enhancing the immunogenic potential of dying cancer cells in vivo (98, 99). The dogmatic view that only necrotic or non-apoptotic (as postulated by the “immunogenic death” concept) cancer cells are characterized by an elevated immunogenic potential started to be questioned by a series of studies published between 2005 and 2007 (41, 70, 100, 101). These publications outlined that cancer cells undergoing apoptosis in response to specific anticancer therapies are immunogenic [a subroutine termed immunogenic cell death (ICD)], as long as they emit precise DAMPs in a spatiotemporally defined fashion (26, 102, 103). Cells succumbing to ICD are sufficient for the elicitation of durable anti-tumor immune responses (1, 26, 53, 102, 104). ICD is indeed paralleled by the redirection and emission of DAMPs, owing to the stimulation of distinct danger signaling pathways occurring in synchrony with cell death signaling (103). Table 2 summarizes the main signaling pathways that play a role in the trafficking and emission of DAMPs. ICD-associated DAMPs and other immunostimulatory factors released by cells destined to undergo ICD favor the establishment of a productive interface between dying cancer cells and innate immune cells (like DCs or macrophages), thereby leading to the initiation of a therapeutically relevant adaptive immune response (Figure 1) (102, 105). In some contexts, DAMPs may regulate the function of specific innate immune cell subsets, e.g., following anthracycline treatment, extracellular adenosine triphosphate (ATP) assists in recruitment and differentiation of CD11c+Cd11b+Ly6Chigh cells into CD11c+CD86+MHCII+ DCs (106); similarly, necrosis associated F-actin exposure activates an immune response by directing the dead cell debris to specifically CD8α+ DCs (59, 107). Indeed, DCs and other antigen-presenting cells exposed to cancer cells succumbing to ICD can then prime CD4+ T cells (and polarize them into TH1, TH17, or TH1/TH17-like phenotype), CD8+ cytotoxic T lymphocytes (CTLs) and γδ T lymphocytes against one or several TAAs (Figure 1) (102). Of note, residual cancer cells that survive ICD inducers can also show some enduring immunogenic characteristics that make them susceptible to immunological control by CTLs (108110).

TABLE 2
www.frontiersin.org

Table 2. Danger signaling pathways characterized as traffickers of DAMPs.

FIGURE 1
www.frontiersin.org

Figure 1. The molecular complexity of immunogenic cell death in cancer. Cancer cells undergoing immunogenic cell death (ICD) emit danger signals for establishing a productive interface with components of the host immune system, including dendritic cells (DCs). DCs exposed to cancer cells succumbing to ICD “prime” the adaptive arm of the immune system, consisting of various effector T-cell populations, which in turn targets therapy-resistant cancer cells. Various molecules are critical for the execution of these processes. The molecular network of ICD-relevant proteins was build using the STRING modeling database (http://string-db.org/) (126).

Immunogenic Cell Death Inducers

Over the past few years, a number of single-agent ICD inducers have been discovered, encompassing conventional chemotherapeutics, targeted anticancer agents and various other ­biological and physicochemical therapies (18, 102, 104, 127). Table 3 summarizes single-agent ICD inducers characterized so far, as per consensus guidelines (104), and the spectra of DAMPs and other immunostimulatory signals associated with them. For combinatorial therapeutic strategies capable of achieving ICD, readers may want to refer to other recent publications (18, 128, 129). It is clear that a general structure–function relationship capable of clustering all existing ICD inducers and predicting new ones does not exist (130), an issue that makes discovering new ICD-inducing therapies based on cheminformatic analyses challenging, if not impossible. A peculiar characteristic of most, if not all, ICD inducers is their ability to induce reactive oxygen species (ROS)-based/associated endoplasmic reticulum (ER) stress, as first delineated for anthracyclines (30, 34, 35, 42, 123, 131133). This peculiarity was exploited for the targeted discovery of hypericin-based photodynamic therapy (Hyp-PDT) – a therapeutic modality that can trigger ICD through the induction of ROS that target the ER (35, 116, 134). Along with an ever more precise characterization of the links between ROS, ER stress, and ICD induction (135, 136), it became clear that the more “focused” ER stress is, the higher the probability of inducing ICD (3, 26, 53, 137). These observations paved way for a classification system based on how ICD inducers engage ER stress for cell death and danger signaling (3, 26, 53, 138). Based on this classification, Type I ICD inducers are defined as anticancer agents that act on non-ER proteins for the induction of cell death, but promote collateral ER stress for danger signaling, thereby operating on multiple targets (3, 26, 53), while Type II ICD inducers are anticancer agents that target the ER for both cell death induction and danger signaling (3, 26, 53). Table 4 summarizes the classification of current ICD inducers into Type I and Type II, and their cell death/danger signaling targets. Such a classification suggest that while Type I ICD inducers can be discovered through various approaches (e.g., DAMP-based drug screening platforms) (130, 139), putative Type II ICD inducers can be characterized rapidly on the basis of their ability to selectively or predominantly target the ER. Recent findings comforted the purpose and usefulness of this classification system, as two novel Type II ICD inducers [i.e., PtII N-heterocyclic carbene complex (140) and Newcastle disease virotherapy (NDV) (43)] were identified based on the notion that they induce predominant ROS-based ER stress (138). Nevertheless, as more ICD inducers and features are discovered, this classification system is expected to evolve or be substituted by a more refined one.

TABLE 3
www.frontiersin.org

Table 3. A list of prominent single-agent immunogenic cell death (ICD) inducers in cancer and their specific associations with danger signaling and other immunostimulatory signaling.

TABLE 4
www.frontiersin.org

Table 4. Classification of ICD inducers into Type I and Type II based on their ER or non-ER-targeting modus operandi.

Since its discovery, a plethora of molecular and immunological components responsible for ICD have been discovered (Figure 1) (26, 102, 188). Table 5 summarizes the molecular and immunological determinants of ICD characterized so far, as well as the models of ICD in which they operate (in a positive, negative or dispensable manner). Anthracyclines and oxaliplatin are the most common ICD inducers employed in experimental settings, followed by Hyp-PDT. According to current understanding, cancer cell-associated determinants of ICD can be subdivided into those that are common to all ICD inducers (i.e., “core” signaling components), and those that operate in an ICD inducer-dependent manner (i.e., “private” signaling components) (26, 189). Thus, eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3, best known as PERK) and the ER-to-Golgi secretory machinery are considered “core” signaling components on the cancer cell side (26, 102). Similarly, from the immune system side, a general role for (IFNγ-producing) CD4+ and CD8+ T cells has been confirmed for most, if not all, ICD inducers (Table 5). Interestingly, some components that are required for ICD induction by some agents (like autophagy for anthracyclines and oxaliplatin) (190) might be either dispensable for ICD induction by other agents, e.g., autophagy for NDV (43) and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), caspase-8 (CASP8) activation or cytosolic Ca2+ levels for Hyp-PDT (35); or even negatively regulate ICD in some settings, e.g., autophagy in case of Hyp-PDT (34) (Table 5). Thus, it will be important to expand our molecular knowledge of ICD to as many experimental settings as possible.

TABLE 5
www.frontiersin.org

Table 5. A list of molecular and immunological components crucial for regulation of ICD.

Immunogenic Cell Death from Bench to Bedside

The relevance of ICD has been verified in a number of rodent models, with a variety of chemical and physicochemical ICD inducers (26, 102). Table 6 summarizes the most prominent mouse or rat models used so far for the characterization and study of ICD. For the moment, ICD has been mostly investigated in heterotopic syngeneic subcutaneous models (195). Within such models, inter-species differences (mouse versus rats), inter-strain differences (among BALB/c, C57BL/6, C3H and KMF mice), and inter-cell line differences, as well as differences in therapeutic setups (prophylactic versus curative) have been amply accounted for (Table 6). Nevertheless, there is predominance in the use of cancer cells derived from carcinogen-induced tumors and transplanted subcutaneously (Table 6). In very few cases, ICD has been characterized in either orthotopic (for NDV) or spontaneous (for anthracyclines) tumor murine models (Table 6). This has been questioned as a prominent Achilles’ heel of ICD research (195). While this criticism is valid, it has to be recognized that no rodent model is perfect at all immunological levels (196).

TABLE 6
www.frontiersin.org

Table 6. A list of prominent preclinical mice or rat models used for analysis of ICD.

As a recent systematic review summarized (196), heterotopic murine models suffer from a number of caveats, including the inability to recapitulate the early interaction between transformed cells and the immune system and the incompatibility between the cancer type and the site-of-transplantation (196). Orthotopic murine models are useful as they overcome the cancer cell-tissue type incompatibility issue (196). While genetically engineered tumor murine models (GEMMs) overcome most of the issues mentioned above, they come with their own set of shortcomings, including a limited genetic mosaicism, a low tumor heterogeneity, a lack of well-defined immunogenic TAAs, the presence of unintended “passenger” genetic modifications, and a reduced mutational spectrum (196). Many of these parameters are critical for responses to immunotherapy/ICD. For instance, the lack of well-defined immunogenic TAAs was the reason why preliminary results obtained in spontaneously developing murine tumors disputed the very existence of TAAs (11). Similarly, a high mutational spectrum (which produces considerable amounts of neo-antigens) has been found to be mandatory for the clinical efficacy of checkpoint blockers (209). Last (but not least), laboratory rodent models in general are associated with some critical issues, including the fact that a high level of inbreeding (which produces a number of shortcomings e.g., homozygous recessive defects) reduces the general immunological fitness, responsiveness and diversity in these models (196, 210, 211). Moreover, numerous immunological differences between mouse and humans tend to affect the translational relevance of the findings obtained (26, 211, 212). Also, the time frames of tumor growth rates between rodent models and humans are relatively divergent (196, 213, 214). This further complicates clinical translation of immunotherapeutic paradigms since the level of immunosurveillance and immunoediting experienced by human tumors can be much higher than any rodent tumor model.

In summary, it would be ideal to test ICD across as many different rodent models as possible, in order to determine the features that can be exploited for therapeutic purposes in humans. Moreover, if ICD fails in a specific experimental model, active effort should be made to characterize the mechanisms behind such failure, since resistance phenotypes can have profound clinical implications. This emerges from various studies summarized in Table 7. Indeed, several ICD resistance mechanisms exist operating at both the cancer cell and the immune system level, which have been characterized in different experimental models. Several of these resistance mechanisms have also been identified in cancer patients, thereby justifying further studies along these lines Table 7.

TABLE 7
www.frontiersin.org

Table 7. Existence of intrinsic or naturally occurring resistance to ICD in experimental cancer models.

A considerable amounts of clinical findings support the relevance of ICD or ICD-related signatures in (at least subsets of) cancer patients. As summarized in Table 8, various ICD-linked (specific) parameters have been associated with the prognosis of cancer patients treated with clinically relevant ICD inducers (like anthracyclines, oxaliplatin, paclitaxel, or radiotherapy). Moreover, it is becoming clear that ICD-related or ICD-derived (immunological) genetic signatures (e.g., a MX1-centered metagene, a CXCR3-PRF1-CASP1-centered metagene, an ASAH1-centered metagene) can be positively associated with good prognosis in patients affected by various neoplasms, including breast, lung, and ovarian malignancies (141, 188, 220). These observations indicate that ICD or ICD-relevant parameters may have prognostic or predictive relevance in at least a subset of cancer patients. It will be important to characterize new and more specific ICD-associated parameters linked to patient prognosis as well as biomarkers that may predict improved disease outcome in cancer patient treated with ICD inducers. Of note, considering the current clinical experience with immunotherapies (209, 221), the patients with an increased likelihood to benefit from ICD inducers are probably those that display pre-existing (baseline) immune reactivity against cancer cells (220, 222, 223). This may depend on the ability of ICD to reboot and/or revive pre-existing TAA-directed immunity rather to prime de novo immune reactivity (5, 191, 224). In future, it would be crucial to characterize biomarkers that allow clinicians to delineate patients with reduced baseline immune reactivity against malignant cells so that proper combinatorial therapies involving ICD inducers can be implemented.

TABLE 8
www.frontiersin.org

Table 8. A list of clinical observations supporting the existence of ICD in cancer patients.

Confronting the Clinical Realities of Anti-Tumor Immunity

It is well-established that the response of cancer patients to immunotherapy relies on the activity of effector T cells [that employ their T-cell receptors (TCRs) for recognizing TAAs]. However, these TAA-targeting T cells may also constitute obstacles for effective anti-tumor immunity (234). As opposed to T lymphocytes recognizing pathogen-associated antigens (PAAs) (Figure 2), indeed, T cells directed against some TAAs (derived from non-mutated proteins that are source of self or near-to-self antigens) are developmentally subjected to negative selection in the thymus and peripheral lymphoid organs (234, 235) (Figure 2). As a result, T cells bearing TCRs with high affinity for self antigens (including some TAAs) are clonally deleted to avoid auto-immunity (234237) (Figure 2). However, some “leakiness” in this process allows TAA-specific T cells possessing TCRs with low affinity to escape deletion (234, 236, 237) and persist, although at low precursor frequencies (238) (Figure 2). Unfortunately, as compared to PAA-specific T cells, which bear high-affinity TCRs (Figure 2), TAA-specific T cells exhibit limited effector and memory functions (234, 239). Coupled with the tendency of progressing tumors to generate a highly immunosuppressive microenvironment, this renders the insurgence of lifelong protective immunity nearly impossible (234). Of note, central and peripheral tolerance may not affect T cells reactive toward neo-tumor-specific antigens (neo-TSAs) e.g., tumor-specific neo-antigens that are generated de novo in the course of tumor progression because of mutational events (240, 241). However, the extent to which such neo-TSAs can elicit consistent “immunodominant” T cell reactivity is still a matter of investigation (240, 241). Nevertheless, in this context, inefficient T-cell stimulation can be overcome through the ICD-based improvement of effector T-cell functions (102). ICD can be further combined with checkpoint-blocking therapies, which potently reverse immunosuppression (209, 242). However, the lifelong maintenance of anti-tumor T cells remains a particularly hard challenge.

FIGURE 2
www.frontiersin.org

Figure 2. Population dynamics of antigen-specific T cells during an immune response to infection or cancer. (A) T cells capable of putatively recognizing non-self, pathogen-associated antigens (PAAs) are not exposed to negative selection in the thymus or peripheral organs like lymph nodes. This allows for the constitutive presence of T lymphocytes bearing high-affinity T-cell receptor (TCR) in naïve conditions. Upon infection, these cells undergo robust expansion and acquire potent effector functions, hence driving an immune response that clears the pathogen and PAAs. Finally, PAA-specific T cells undergo contraction along with the establishment of immunological memory. To a limited extent, T cells reacting against PAAs expressed by virus-induced tumors may exhibit similar (although not identical) responses. (B) T cells that may recognize self or close-to-self antigens expressed by virus-unrelated malignancies undergo robust negative selection in the thymus and lymph nodes. Thus, all putative T lymphocytes bearing a high-affinity TCR against tumor-associated antigens (TAAs) are eliminated. However, some leakiness in this process allows for the persistence of TAA-specific T lymphocytes with low-affinity TCR, although at very low precursor frequencies. This is one of the reasons why in some individuals immunosurveillance at some stage fails to impede tumor progression. As malignant lesions progress, the amount of TAAs increases, causing a weak rise in TAA-specific T cells. However, tumor progression is generally coupled with the establishment of robust immunosuppressive networks that potently inhibit such TAA-targeting T cells. In this context, the administration of immunogenic cell death (ICD) according to a schedule that does not lead to lymphodepletion can favor the stimulation of TAA-targeting T cells and (re)instate immunosurveillance. Combining ICD inducers with checkpoint-blocking agents may further boost TAA-targeting immune responses. However, these treatments may not ensure the lifelong persistence of TAA-recognizing T cells, some of which are susceptible to elimination through tolerance mechanisms. Anticancer vaccines may counteract, at least to some extent, such loss. The figure was partly inspired from Baitsch et al. (234).

In the clinical reality, anticancer agents are administered to patients in a limited number of cycles. Even if these therapeutic regimens may attain optimal efficacy in terms of ICD induction, they are unlikely to ensure the lifelong persistence of TAA-directed T cells with low-affinity TCR (234, 243). This probably reflects the contraction of TAA-targeting T cells occurring once the immunostimulatory stimulus provided by ICD ceases, owing to peripheral tolerance mechanisms (234). Clinically, it may not be feasible to administer ICD inducers repeatedly over time, since many of them can cause lymphopenia (which negatively affects disease outcome), or are associated with other side effects (244). It has been proposed that active immunization with ICD-based anticancer vaccines (which are associated with robust immunogenicity) given in a repetitive manner may achieve this goal (Figure 2) (234, 243, 245). Thus, it will be important to test whether the long-term administration of ICD-based anticancer vaccines can sustain the effector function of TAA-specific T cells bearing low-affinity TCRs, hence, ensuring lifelong disease-free survival. Of note, in the case of hematological malignancies, this issue could be overcome upon the adoptive transfer of CTLs expressing chimeric antigen receptors (CARs) (1). However, whether CAR-expressing CTLs generate protective immunological memory in the absence of considerable side effects remains to be determined. Moreover, the use of this therapeutic strategy against solid malignancies is relatively challenging owing to lack of well-defined “unique” TAAs (1, 246).

Conclusion

The model of ICD has been considerably refined since the initial identification of a cell death modality manifesting apoptotic features but able to induce an adaptive immune response. This model strives to integrate several phenomena observed throughout the second half of the twentieth century in one therapeutically relevant platform. However, as discussed above, several challenges still need to be addressed. First, comprehensive testing should be performed in advanced experimental settings like GEMMs or orthotopic tumor models. Second, ICD resistance mechanisms should be characterized with precision. Third, various issues linked to the successful translation of ICD to cancer therapy will have to be resolved, including (but not limited to) treatment schedules, dosages, and combinatorial strategies. This translational drive also needs to be coupled with effective strategies for the discovery of new and effective ICD inducers. Drug screening programs are often complicated by the possibility of false-positive (due to bystander presence of DAMPs) (30) or false-negative (due to limited number of biomarkers used for screening) hits. This issue can only be ironed out by discovering new and common regulators of ICD, and integrating them into existing screening platforms. Last, but not least, it will be important to identify new ICD-related/derived biomarkers that can be used to improve current protocols of patient stratification and clinical decision making. We are positive that all these objectives are at reach.

Author Contributions

ADG did the literature study, data collection, as well as conceived and wrote the manuscript. PA provided senior supervision and guidance, conceived the paper, helped in writing, and critically revised the manuscript. LG improved and edited the manuscript. JMBSP helped with the preparation of figures. All authors participated in the critical reading of the manuscript (wherever applicable), approved content and conclusions, as well as helped in ensuring the accuracy of cited literature.

Conflict of Interest Statement

Akseli Hemminki is shareholder in Targovax AG and TILT Biotherapeutics Ltd. The remaining authors have no conflict of interest to declare.

Acknowledgments

We would like to explicitly declare that this manuscript does not aim to describe guidelines for the fields of ICD and DAMP research. Rather, it is meant to be a comprehensive classification and review of relevant literature expressing consensus discussions, opinions, and conclusions endorsed and/or supported by a number of researchers and clinicians investigating ICD and DAMPs. We would also like to acknowledge the following colleagues for their support, reading and/or positive appraisal of this manuscript: Wee Han Ang, Vincenzo Barnaba, Marco E. Bianchi, Karin de Visser, Sandra O. Gollnick, Peter Henson, Polly Matzinger, Marek Michalak, Kodi Ravichandran, and Andrew Thorburn. ADG is a recipient of the FWO postdoctoral fellowship 2013. This work was supported by grants from the Fund for Scientific Research Flanders (FWO-Vlaanderen; G.0661.09, G.0728.10 and G.0584.12N) and KU Leuven (GOA/11/009) to PA; This paper presents research results of the IAP7/32, funded by the Interuniversity Attraction Poles Programme, initiated by the Belgian State, Science Policy Office.

Abbreviations

DAMP, damage-associated molecular pattern; DC, dendritic cell; ER, endoplasmic reticulum; GEMM, genetically engineered murine model; HSP, heat shock protein; Hyp, hypericin; ICD, immunogenic cell death; NDV, Newcastle disease virotherapy; PDT, photodynamic therapy; ROS, reactive oxygen species.

References

1. Galluzzi L, Vacchelli E, Bravo-San Pedro JM, Buque A, Senovilla L, Baracco EE, et al. Classification of current anticancer immunotherapies. Oncotarget (2014) 5(24):12472–508. doi:10.18632/oncotarget.2998

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Kepp O, Tesniere A, Zitvogel L, Kroemer G. The immunogenicity of tumor cell death. Curr Opin Oncol (2009) 21(1):71–6. doi:10.1097/CCO.0b013e32831bc375

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Garg AD, Dudek AM, Agostinis P. Cancer immunogenicity, danger signals, and DAMPs: what, when, and how? Biofactors (2013) 39(4):355–67. doi:10.1002/biof.1125

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Blankenstein T, Coulie PG, Gilboa E, Jaffee EM. The determinants of tumour immunogenicity. Nat Rev Cancer (2012) 12(4):307–13. doi:10.1038/nrc3246

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta (2010) 1805(1):53–71. doi:10.1016/j.bbcan.2009.08.003

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol (2014) 15(7):e257–67. doi:10.1016/S1470-2045(13)70585-0

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Chiang CL, Kandalaft LE, Coukos G. Adjuvants for enhancing the immunogenicity of whole tumor cell vaccines. Int Rev Immunol (2011) 30(2–3):150–82. doi:10.3109/08830185.2011.572210

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Parish CR. Cancer immunotherapy: the past, the present and the future. Immunol Cell Biol (2003) 81(2):106–13. doi:10.1046/j.0818-9641.2003.01151.x

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci (1893) 105:487–511. doi:10.1097/00000441-189305000-00001

CrossRef Full Text | Google Scholar

10. Tsung K, Norton JA. Lessons from Coley’s toxin. Surg Oncol (2006) 15(1):25–8. doi:10.1016/j.suronc.2006.05.002

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer (2014) 14(2):135–46. doi:10.1038/nrc3670

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Liao SK, Carr DH. Comparative immunogenicity of irradiated, neuraminidase treated, and fused cells of a strain-restricted sarcoma. Z Krebsforsch klin Onkol Cancer Res Clin Oncol (1974) 82(2):133–42.

Google Scholar

13. Milas L, Withers HR. Nonspecific immunotherapy of malignant tumors. Radiology (1976) 118(1):211–8. doi:10.1148/118.1.211

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Bogden AE, Esber HJ. Influence of surgery, irradiation, chemotherapy, and immunotherapy on growth of a metastasizing rat mammary adenocarcinoma. Natl Cancer Inst Monogr (1978) (49):97–100.

PubMed Abstract | Google Scholar

15. Dickson JA, Shah SA. Hyperthermia: the immune response and tumor metastasis. Natl Cancer Inst Monogr (1982) 61:183–92.

PubMed Abstract | Google Scholar

16. Suit HD, Walker AM. Assessment of the response of tumours to radiation: clinical and experimental studies. Br J Cancer Suppl (1980) 4:1–10.

PubMed Abstract | Google Scholar

17. Richert L, Or A, Shinitzky M. Promotion of tumor antigenicity in EL-4 leukemia cells by hydrostatic pressure. Cancer Immunol Immunother (1986) 22(2):119–24. doi:10.1007/BF00199125

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov (2012) 11(3):215–33. doi:10.1038/nrd3626

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol (2009) 9(5):353–63. doi:10.1038/nri2545

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol (1994) 12:991–1045. doi:10.1146/annurev.iy.12.040194.005015

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Matzinger P. The danger model: a renewed sense of self. Science (2002) 296(5566):301–5. doi:10.1126/science.1071059

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Land W, Schneeberger H, Schleibner S, Illner WD, Abendroth D, Rutili G, et al. The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation (1994) 57(2):211–7. doi:10.1097/00007890-199401001-00010

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol (2004) 4(6):469–78. doi:10.1038/nri1372

CrossRef Full Text | Google Scholar

24. Rubartelli A, Lotze MT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol (2007) 28(10):429–36. doi:10.1016/j.it.2007.08.004

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Li G, Tang D, Lotze MT. Menage a trois in stress: DAMPs, redox and autophagy. Semin Cancer Biol (2013) 23(5):380–90. doi:10.1016/j.semcancer.2013.08.002

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Garg AD, Martin S, Golab J, Agostinis P. Danger signalling during cancer cell death: origins, plasticity and regulation. Cell Death Differ (2014) 21(1):26–38. doi:10.1038/cdd.2013.48

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol (2007) 81(1):1–5. doi:10.1189/jlb.0306164

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Bondanza A, Zimmermann VS, Rovere-Querini P, Turnay J, Dumitriu IE, Stach CM, et al. Inhibition of phosphatidylserine recognition heightens the immunogenicity of irradiated lymphoma cells in vivo. J Exp Med (2004) 200(9):1157–65. doi:10.1084/jem.20040327

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Stach CM, Turnay X, Voll RE, Kern PM, Kolowos W, Beyer TD, et al. Treatment with annexin V increases immunogenicity of apoptotic human T-cells in Balb/c mice. Cell Death Differ (2000) 7(10):911–5. doi:10.1038/sj.cdd.4400715

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Dudek-Peric AM, Ferreira GB, Muchowicz A, Wouters J, Prada N, Martin S, et al. Antitumor immunity triggered by melphalan is potentiated by melanoma cell surface-associated calreticulin. Cancer Res (2015) 75(8):1603–14. doi:10.1158/0008-5472.CAN-14-2089

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Rondas D, Crevecoeur I, D’Hertog W, Ferreira GB, Staes A, Garg AD, et al. Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes. Diabetes (2015) 64(2):573–86. doi:10.2337/db14-0621

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Venereau E, Casalgrandi M, Schiraldi M, Antoine DJ, Cattaneo A, De Marchis F, et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med (2012) 209(9):1519–28. doi:10.1084/jem.20120189

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Weyd H, Abeler-Dorner L, Linke B, Mahr A, Jahndel V, Pfrang S, et al. Annexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity. PLoS One (2013) 8(4):e62449. doi:10.1371/journal.pone.0062449

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Garg AD, Dudek AM, Ferreira GB, Verfaillie T, Vandenabeele P, Krysko DV, et al. ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy (2013) 9(9):1292–307. doi:10.4161/auto.25399

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J (2012) 31(5):1062–79. doi:10.1038/emboj.2011.497

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med (2009) 15(10):1170–8. doi:10.1038/nm.2028

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature (2009) 461(7261):282–6. doi:10.1038/nature08296

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Iwata A, Morgan-Stevenson V, Schwartz B, Liu L, Tupper J, Zhu X, et al. Extracellular BCL2 proteins are danger-associated molecular patterns that reduce tissue damage in murine models of ischemia-reperfusion injury. PLoS One (2010) 5(2):e9103. doi:10.1371/journal.pone.0009103

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Babelova A, Moreth K, Tsalastra-Greul W, Zeng-Brouwers J, Eickelberg O, Young MF, et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem (2009) 284(36):24035–48. doi:10.1074/jbc.M109.014266

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Schaefer L. Extracellular matrix molecules: endogenous danger signals as new drug targets in kidney diseases. Curr Opin Pharmacol (2010) 10(2):185–90. doi:10.1016/j.coph.2009.11.007

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med (2007) 13(1):54–61. doi:10.1038/nm1523

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Garg AD, Elsen S, Krysko DV, Vandenabeele P, de Witte P, Agostinis P. Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal. Oncotarget (2015) 6(29):26841–60. doi:10.18632/oncotarget.4754

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Koks CA, Garg AD, Ehrhardt M, Riva M, Vandenberk L, Boon L, et al. Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death. Int J Cancer (2015) 136(5):E313–25. doi:10.1002/ijc.29202

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell (2005) 123(2):321–34. doi:10.1016/j.cell.2005.08.032

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Garcia Fernandez M, Troiano L, Moretti L, Nasi M, Pinti M, Salvioli S, et al. Early changes in intramitochondrial cardiolipin distribution during apoptosis. Cell Growth Differ (2002) 13(9):449–55.

PubMed Abstract | Google Scholar

46. Sorice M, Circella A, Cristea IM, Garofalo T, Di Renzo L, Alessandri C, et al. Cardiolipin and its metabolites move from mitochondria to other cellular membranes during death receptor-mediated apoptosis. Cell Death Differ (2004) 11(10):1133–45. doi:10.1038/sj.cdd.4401457

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Korbelik M, Banath J, Sun J, Canals D, Hannun YA, Separovic D. Ceramide and sphingosine-1-phosphate act as photodynamic therapy-elicited damage-associated molecular patterns: cell surface exposure. Int Immunopharmacol (2014) 20(2):359–65. doi:10.1016/j.intimp.2014.03.016

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Horino K, Nishiura H, Ohsako T, Shibuya Y, Hiraoka T, Kitamura N, et al. A monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells. Lab Invest (1998) 78(5):603–17.

PubMed Abstract | Google Scholar

49. Nishimura T, Horino K, Nishiura H, Shibuya Y, Hiraoka T, Tanase S, et al. Apoptotic cells of an epithelial cell line, AsPC-1, release monocyte chemotactic S19 ribosomal protein dimer. J Biochem (2001) 129(3):445–54. doi:10.1093/oxfordjournals.jbchem.a002876

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Peter C, Wesselborg S, Lauber K. Role of attraction and danger signals in the uptake of apoptotic and necrotic cells and its immunological outcome. In: Krysko DV, Vandenabeele P, editors. Phagocytosis of Dying Cells. Berlin: Springer Science + Business Media B.V. (2009). p. 63–101.

Google Scholar

51. Yamamoto T. Roles of the ribosomal protein S19 dimer and the C5a receptor in pathophysiological functions of phagocytic leukocytes. Pathol Int (2007) 57(1):1–11. doi:10.1111/j.1440-1827.2007.02049.x

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Struck J, Uhlein M, Morgenthaler NG, Furst W, Hoflich C, Bahrami S, et al. Release of the mitochondrial enzyme carbamoyl phosphate synthase under septic conditions. Shock (2005) 23(6):533–8.

PubMed Abstract | Google Scholar

53. Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer (2012) 12(12):860–75. doi:10.1038/nrc3380

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Pullerits R, Bokarewa M, Jonsson IM, Verdrengh M, Tarkowski A. Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology (Oxford) (2005) 44(1):32–9. doi:10.1093/rheumatology/keh406

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Codina R, Vanasse A, Kelekar A, Vezys V, Jemmerson R. Cytochrome c-induced lymphocyte death from the outside in: inhibition by serum leucine-rich alpha-2-glycoprotein-1. Apoptosis (2010) 15(2):139–52. doi:10.1007/s10495-009-0412-0

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Yoon KW, Byun S, Kwon E, Hwang SY, Chu K, Hiraki M, et al. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science (2015) 349(6247):1261669. doi:10.1126/science.1261669

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Kao J, Houck K, Fan Y, Haehnel I, Libutti SK, Kayton ML, et al. Characterization of a novel tumor-derived cytokine. Endothelial-monocyte activating polypeptide II. J Biol Chem (1994) 269(40):25106–19.

PubMed Abstract | Google Scholar

58. Knies UE, Behrensdorf HA, Mitchell CA, Deutsch U, Risau W, Drexler HC, et al. Regulation of endothelial monocyte-activating polypeptide II release by apoptosis. Proc Natl Acad Sci U S A (1998) 95(21):12322–7. doi:10.1073/pnas.95.21.12322

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Ahrens S, Zelenay S, Sancho D, Hanc P, Kjaer S, Feest C, et al. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity (2012) 36(4):635–45. doi:10.1016/j.immuni.2012.03.008

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol (2012) 13(9):832–42. doi:10.1038/ni.2376

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Zitvogel L, Kepp O, Kroemer G. Decoding cell death signals in inflammation and immunity. Cell (2010) 140(6):798–804. doi:10.1016/j.cell.2010.02.015

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Pletjushkina OY, Fetisova EK, Lyamzaev KG, Ivanova OY, Domnina LV, Vyssokikh MY, et al. Long-distance apoptotic killing of cells is mediated by hydrogen peroxide in a mitochondrial ROS-dependent fashion. Cell Death Differ (2005) 12(11):1442–4. doi:10.1038/sj.cdd.4401685

CrossRef Full Text | Google Scholar

63. Garg AD, Nowis D, Golab J, Agostinis P. Photodynamic therapy: illuminating the road from cell death towards anti-tumour immunity. Apoptosis (2010) 15(9):1050–71. doi:10.1007/s10495-010-0479-7

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Suzuki S, Kulkarni AB. Extracellular heat shock protein HSP90beta secreted by MG63 osteosarcoma cells inhibits activation of latent TGF-beta1. Biochem Biophys Res Commun (2010) 398(3):525–31. doi:10.1016/j.bbrc.2010.06.112

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Korbelik M, Sun J, Cecic I. Photodynamic therapy-induced cell surface expression and release of heat shock proteins: relevance for tumor response. Cancer Res (2005) 65(3):1018–26.

PubMed Abstract | Google Scholar

66. Cirone M, Di Renzo L, Lotti LV, Conte V, Trivedi P, Santarelli R, et al. Primary effusion lymphoma cell death induced by bortezomib and AG 490 activates dendritic cells through CD91. PLoS One (2012) 7(3):e31732. doi:10.1371/journal.pone.0031732

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Zunino B, Rubio-Patino C, Villa E, Meynet O, Proics E, Cornille A, et al. Hyperthermic intraperitoneal chemotherapy leads to an anticancer immune response via exposure of cell surface heat shock protein 90. Oncogene (2015). doi:10.1038/onc.2015.82

CrossRef Full Text | Google Scholar

68. Zhou Z, Yamamoto Y, Sugai F, Yoshida K, Kishima Y, Sumi H, et al. Hepatoma-derived growth factor is a neurotrophic factor harbored in the nucleus. J Biol Chem (2004) 279(26):27320–6. doi:10.1074/jbc.M308650200

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Huang H, Evankovich J, Yan W, Nace G, Zhang L, Ross M, et al. Endogenous histones function as alarmins in sterile inflammatory liver injury through toll-like receptor 9 in mice. Hepatology (2011) 54(3):999–1008. doi:10.1002/hep.24501

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med (2007) 13(9):1050–9. doi:10.1038/nm1622

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Semino C, Angelini G, Poggi A, Rubartelli A. NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood (2005) 106(2):609–16. doi:10.1182/blood-2004-10-3906

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature (2002) 418(6894):191–5. doi:10.1038/nature00858

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Thorburn J, Horita H, Redzic J, Hansen K, Frankel AE, Thorburn A. Autophagy regulates selective HMGB1 release in tumor cells that are destined to die. Cell Death Differ (2009) 16(1):175–83. doi:10.1038/cdd.2008.143

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Yang D, Postnikov YV, Li Y, Tewary P, de la Rosa G, Wei F. High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses. J Exp Med (2012) 209(1):157–71. doi:10.1084/jem.20101354

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Cohen I, Rider P, Carmi Y, Braiman A, Dotan S, White MR, et al. Differential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc Natl Acad Sci U S A (2010) 107(6):2574–9. doi:10.1073/pnas.0915018107

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Vanden Berghe T, Kalai M, Denecker G, Meeus A, Saelens X, Vandenabeele P. Necrosis is associated with IL-6 production but apoptosis is not. Cell Signal (2006) 18(3):328–35. doi:10.1016/j.cellsig.2005.05.003

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG, Lindemann RK, et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell (2003) 113:717–30. doi:10.1016/S0092-8674(03)00422-7

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature (2010) 464(7285):104–7. doi:10.1038/nature08780

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Collins LV, Hajizadeh S, Holme E, Jonsson IM, Tarkowski A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol (2004) 75(6):995–1000. doi:10.1189/jlb.0703328

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Galluzzi L, Kepp O, Kroemer G. Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol (2012) 13(12):780–8. doi:10.1038/nrm3479

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature (2003) 425(6957):516–21. doi:10.1038/nature01991

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Carp H. Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils. J Exp Med (1982) 155(1):264–75. doi:10.1084/jem.155.1.264

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Rabiet MJ, Huet E, Boulay F. The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview. Biochimie (2007) 89(9):1089–106. doi:10.1016/j.biochi.2007.02.015

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Czapiga M, Gao JL, Kirk A, Lekstrom-Himes J. Human platelets exhibit chemotaxis using functional N-formyl peptide receptors. Exp Hematol (2005) 33(1):73–84. doi:10.1016/j.exphem.2004.09.010

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Moghaddam AE, Gartlan KH, Kong L, Sattentau QJ. Reactive carbonyls are a major Th2-inducing damage-associated molecular pattern generated by oxidative stress. J Immunol (2011) 187(4):1626–33. doi:10.4049/jimmunol.1003906

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res (2011) 108(2):235–48. doi:10.1161/CIRCRESAHA.110.223875

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Vandenberk L, Garg AD, Verschuere T, Koks C, Belmans J, Beullens M, et al. Irradiation of necrotic cancer cells employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma. Oncoimmunology (2015). doi:10.1080/2162402X.2015.1083669

CrossRef Full Text | Google Scholar

88. Riddell JR, Wang XY, Minderman H, Gollnick SO. Peroxiredoxin 1 stimulates secretion of proinflammatory cytokines by binding to TLR4. J Immunol (2010) 184(2):1022–30. doi:10.4049/jimmunol.0901945

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Franz S, Herrmann K, Furnrohr BG, Sheriff A, Frey B, Gaipl US, et al. After shrinkage apoptotic cells expose internal membrane-derived epitopes on their plasma membranes. Cell Death Differ (2007) 14(4):733–42. doi:10.1038/sj.cdd.4402066

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Petrovski G, Zahuczky G, Katona K, Vereb G, Martinet W, Nemes Z, et al. Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes. Cell Death Differ (2007) 14(6):1117–28. doi:10.1038/sj.cdd.4402112

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Bratton DL, Fadok VA, Richter DA, Kailey JM, Guthrie LA, Henson PM. Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase. J Biol Chem (1997) 272(42):26159–65. doi:10.1074/jbc.272.42.26159

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, et al. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med (1995) 182(5):1545–56. doi:10.1084/jem.182.5.1545

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Brouckaert G, Kalai M, Krysko DV, Saelens X, Vercammen D, Ndlovu MN, et al. Phagocytosis of necrotic cells by macrophages is phosphatidylserine dependent and does not induce inflammatory cytokine production. Mol Biol Cell (2004) 15(3):1089–100. doi:10.1091/mbc.E03-09-0668

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Donato R. RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr Mol Med (2007) 7(8):711–24. doi:10.2174/156652407783220688

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Goh FG, Piccinini AM, Krausgruber T, Udalova IA, Midwood KS. Transcriptional regulation of the endogenous danger signal tenascin-C: a novel autocrine loop in inflammation. J Immunol (2010) 184(5):2655–62. doi:10.4049/jimmunol.0903359

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Krispin A, Bledi Y, Atallah M, Trahtemberg U, Verbovetski I, Nahari E, et al. Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states. Blood (2006) 108(10):3580–9. doi:10.1182/blood-2006-03-013334

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ (2015) 22(1):58–73. doi:10.1038/cdd.2014.137

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Melcher A, Todryk S, Hardwick N, Ford M, Jacobson M, Vile RG. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nat Med (1998) 4(5):581–7. doi:10.1038/nm0598-581

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Gough MJ, Melcher AA, Crittenden MR, Sanchez-Perez L, Voellmy R, Vile RG. Induction of cell stress through gene transfer of an engineered heat shock transcription factor enhances tumor immunogenicity. Gene Ther (2004) 11(13):1099–104. doi:10.1038/sj.gt.3302274

PubMed Abstract | CrossRef Full Text | Google Scholar

100. Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood (2007) 109(11):4839–45. doi:10.1182/blood-2006-10-054221

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med (2005) 202(12):1691–701. doi:10.1084/jem.20050915

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol (2013) 31:51–72. doi:10.1146/annurev-immunol-032712-100008

CrossRef Full Text | Google Scholar

103. Garg AD, Dudek-Peric AM, Romano E, Agostinis P. Immunogenic cell death. Int J Dev Biol (2015) 59:131–40. doi:10.1387/ijdb.150061pa

PubMed Abstract | CrossRef Full Text | Google Scholar

104. Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology (2014) 3(9):e955691. doi:10.4161/21624011.2014.955691

PubMed Abstract | CrossRef Full Text | Google Scholar

105. Dudek AM, Martin S, Garg AD, Agostinis P. Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells interface that augments anticancer immunity. Front Immunol (2014) 4:438. doi:10.3389/fimmu.2013.00438

PubMed Abstract | CrossRef Full Text | Google Scholar

106. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity (2013) 38(4):729–41. doi:10.1016/j.immuni.2013.03.003

PubMed Abstract | CrossRef Full Text | Google Scholar

107. Zhang JG, Czabotar PE, Policheni AN, Caminschi I, Wan SS, Kitsoulis S, et al. The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity (2012) 36(4):646–57. doi:10.1016/j.immuni.2012.03.009

PubMed Abstract | CrossRef Full Text | Google Scholar

108. Garnett CT, Palena C, Chakraborty M, Tsang KY, Schlom J, Hodge JW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res (2004) 64(21):7985–94. doi:10.1158/0008-5472.CAN-04-1525

PubMed Abstract | CrossRef Full Text | Google Scholar

109. Hodge JW, Garnett CT, Farsaci B, Palena C, Tsang KY, Ferrone S, et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer (2013) 133(3):624–36. doi:10.1002/ijc.28070

PubMed Abstract | CrossRef Full Text | Google Scholar

110. Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget (2014) 5(2):403–16. doi:10.18632/oncotarget.1719

PubMed Abstract | CrossRef Full Text | Google Scholar

111. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science (2011) 334(6062):1573–7. doi:10.1126/science.1208347

PubMed Abstract | CrossRef Full Text | Google Scholar

112. Garg AD, Dudek AM, Agostinis P. Calreticulin surface exposure is abrogated in cells lacking, chaperone-mediated autophagy-essential gene, LAMP2A. Cell Death Dis (2013) 4:e826. doi:10.1038/cddis.2013.372

CrossRef Full Text | Google Scholar

113. Martins I, Wang Y, Michaud M, Ma Y, Sukkurwala AQ, Shen S, et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ (2014) 21(1):79–91. doi:10.1038/cdd.2013.75

PubMed Abstract | CrossRef Full Text | Google Scholar

114. Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR, Ferguson TA. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity (2008) 29(1):21–32. doi:10.1016/j.immuni.2008.05.013

PubMed Abstract | CrossRef Full Text | Google Scholar

115. Jube S, Rivera Z, Bianchi ME, Powers A, Wang E, Pagano IS, et al. Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res (2012) 72(13):3290–301. doi:10.1158/0008-5472.CAN-11-3481

PubMed Abstract | CrossRef Full Text | Google Scholar

116. Garg AD, Krysko DV, Vandenabeele P, Agostinis P. Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol Immunother (2012) 61(2):215–21. doi:10.1007/s00262-011-1184-2

PubMed Abstract | CrossRef Full Text | Google Scholar

117. Lancaster GI, Febbraio MA. Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem (2005) 280(24):23349–55. doi:10.1074/jbc.M502017200

PubMed Abstract | CrossRef Full Text | Google Scholar

118. Mambula SS, Calderwood SK. Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol (2006) 177(11):7849–57. doi:10.4049/jimmunol.177.11.7849

PubMed Abstract | CrossRef Full Text | Google Scholar

119. Vega VL, Rodriguez-Silva M, Frey T, Gehrmann M, Diaz JC, Steinem C, et al. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol (2008) 180(6):4299–307. doi:10.4049/jimmunol.180.6.4299

PubMed Abstract | CrossRef Full Text | Google Scholar

120. Kotter B, Frey B, Winderl M, Rubner Y, Scheithauer H, Sieber R, et al. The in vitro immunogenic potential of caspase-3 proficient breast cancer cells with basal low immunogenicity is increased by hypofractionated irradiation. Radiat Oncol (2015) 10(1):197. doi:10.1186/s13014-015-0506-5

PubMed Abstract | CrossRef Full Text | Google Scholar

121. Multhoff G, Botzler C, Wiesnet M, Muller E, Meier T, Wilmanns W, et al. A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int J Cancer (1995) 61(2):272–9. doi:10.1002/ijc.2910610222

PubMed Abstract | CrossRef Full Text | Google Scholar

122. Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res (2005) 65(12):5238–47. doi:10.1158/0008-5472.CAN-04-3804

PubMed Abstract | CrossRef Full Text | Google Scholar

123. Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DC, et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J (2009) 28(5):578–90. doi:10.1038/emboj.2009.1

PubMed Abstract | CrossRef Full Text | Google Scholar

124. Madeo F, Durchschlag M, Kepp O, Panaretakis T, Zitvogel L, Frohlich KU, et al. Phylogenetic conservation of the preapoptotic calreticulin exposure pathway from yeast to mammals. Cell Cycle (2009) 8(4):639–42. doi:10.4161/cc.8.4.7794

PubMed Abstract | CrossRef Full Text | Google Scholar

125. Martin S, Dudek-Peric AM, Maes H, Garg AD, Gabrysiak M, Demirsoy S, et al. Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in vemurafenib-resistant melanoma cells. Biochem Pharmacol (2015) 93(3):290–304. doi:10.1016/j.bcp.2014.12.003

PubMed Abstract | CrossRef Full Text | Google Scholar

126. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res (2015) 43(Database issue):D447–52. doi:10.1093/nar/gku1003

PubMed Abstract | CrossRef Full Text | Google Scholar

127. Dudek AM, Garg AD, Krysko DV, De Ruysscher D, Agostinis P. Inducers of immunogenic cancer cell death. Cytokine Growth Factor Rev (2013) 24(4):319–33. doi:10.1016/j.cytogfr.2013.01.005

PubMed Abstract | CrossRef Full Text | Google Scholar

128. Bezu L, Gomes-de-Silva LC, Dewitte H, Breckpot K, Fucikova J, Spisek R, et al. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol (2015) 6:187. doi:10.3389/fimmu.2015.00187

PubMed Abstract | CrossRef Full Text | Google Scholar

129. Siurala M, Bramante S, Vassilev L, Hirvinen M, Parviainen S, Tahtinen S, et al. Oncolytic adenovirus and doxorubicin-based chemotherapy results in synergistic antitumor activity against soft-tissue sarcoma. Int J Cancer (2015) 136(4):945–54. doi:10.1002/ijc.29048

PubMed Abstract | CrossRef Full Text | Google Scholar

130. Menger L, Vacchelli E, Adjemian S, Martins I, Ma Y, Shen S, et al. Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci Transl Med (2012) 4(143):143ra99. doi:10.1126/scitranslmed.3003807

PubMed Abstract | CrossRef Full Text | Google Scholar

131. Panaretakis T, Joza N, Modjtahedi N, Tesniere A, Vitale I, Durchschlag M, et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ (2008) 15(9):1499–509. doi:10.1038/cdd.2008.67

PubMed Abstract | CrossRef Full Text | Google Scholar

132. Tufi R, Panaretakis T, Bianchi K, Criollo A, Fazi B, Di Sano F, et al. Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin. Cell Death Differ (2008) 15(2):274–82. doi:10.1038/sj.cdd.4402275

PubMed Abstract | CrossRef Full Text | Google Scholar

133. Martins I, Kepp O, Schlemmer F, Adjemian S, Tailler M, Shen S, et al. Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene (2011) 30(10):1147–58. doi:10.1038/onc.2010.500

PubMed Abstract | CrossRef Full Text | Google Scholar

134. Verfaillie T, Rubio N, Garg AD, Bultynck G, Rizzuto R, Decuypere JP, et al. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ (2012) 19(11):1880–91. doi:10.1038/cdd.2012.74

PubMed Abstract | CrossRef Full Text | Google Scholar

135. Galluzzi L, Bravo-San Pedro JM, Kroemer G. Organelle-specific initiation of cell death. Nat Cell Biol (2014) 16(8):728–36. doi:10.1038/ncb3005

PubMed Abstract | CrossRef Full Text | Google Scholar

136. Chaurio RA, Munoz LE, Maueroder C, Janko C, Harrer T, Furnrohr BG, et al. The progression of cell death affects the rejection of allogeneic tumors in immune-competent mice – implications for cancer therapy. Front Immunol (2014) 5:560. doi:10.3389/fimmu.2014.00560

PubMed Abstract | CrossRef Full Text | Google Scholar

137. Garg AD, Maes H, van Vliet AR, Agostinis P. Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress. Mol Cell Oncol (2015) 2(1):e975089. doi:10.4161/23723556.2014.975089

CrossRef Full Text | Google Scholar

138. van Vliet AR, Martin S, Garg AD, Agostinis P. The PERKs of damage-associated molecular patterns mediating cancer immunogenicity: from sensor to the plasma membrane and beyond. Semin Cancer Biol (2015) 33:74–85. doi:10.1016/j.semcancer.2015.03.010

PubMed Abstract | CrossRef Full Text | Google Scholar

139. Sukkurwala AQ, Adjemian S, Senovilla L, Michaud M, Spaggiari S, Vacchelli E, et al. Screening of novel immunogenic cell death inducers within the NCI mechanistic diversity set. Oncoimmunology (2014) 3:e28473. doi:10.4161/onci.28473

PubMed Abstract | CrossRef Full Text | Google Scholar

140. Wong DY, Ong WW, Ang WH. Induction of immunogenic cell death by chemotherapeutic platinum complexes. Angew Chem Int Ed Engl (2015) 54(22):6483–7. doi:10.1002/anie.201500934

PubMed Abstract | CrossRef Full Text | Google Scholar

141. Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med (2014) 20(11):1301–9. doi:10.1038/nm.3708

PubMed Abstract | CrossRef Full Text | Google Scholar

142. Ramakrishnan R, Gabrilovich DI. The role of mannose-6-phosphate receptor and autophagy in influencing the outcome of combination therapy. Autophagy (2013) 9(4):615–6. doi:10.4161/auto.23485

PubMed Abstract | CrossRef Full Text | Google Scholar

143. Kaminski JM, Shinohara E, Summers JB, Niermann KJ, Morimoto A, Brousal J. The controversial abscopal effect. Cancer Treat Rev (2005) 31(3):159–72. doi:10.1016/j.ctrv.2005.03.004

PubMed Abstract | CrossRef Full Text | Google Scholar

144. Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology (2014) 3:e28518. doi:10.4161/onci.28518

PubMed Abstract | CrossRef Full Text | Google Scholar

145. Garrido G, Rabasa A, Sanchez B, Lopez MV, Blanco R, Lopez A, et al. Induction of immunogenic apoptosis by blockade of epidermal growth factor receptor activation with a specific antibody. J Immunol (2011) 187(10):4954–66. doi:10.4049/jimmunol.1003477

PubMed Abstract | CrossRef Full Text | Google Scholar

146. Bugaut H, Bruchard M, Berger H, Derangere V, Odoul L, Euvrard R, et al. Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells. PLoS One (2013) 8(6):e65181. doi:10.1371/journal.pone.0065181

PubMed Abstract | CrossRef Full Text | Google Scholar

147. Diaconu I, Cerullo V, Hirvinen ML, Escutenaire S, Ugolini M, Pesonen SK, et al. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res (2012) 72(9):2327–38. doi:10.1158/0008-5472.CAN-11-2975

PubMed Abstract | CrossRef Full Text | Google Scholar

148. Hemminki O, Parviainen S, Juhila J, Turkki R, Linder N, Lundin J, et al. Immunological data from cancer patients treated with Ad5/3-E2F-Delta24-GMCSF suggests utility for tumor immunotherapy. Oncotarget (2015) 6(6):4467–81. doi:10.18632/oncotarget.2901

PubMed Abstract | CrossRef Full Text | Google Scholar

149. Sun C, Wang H, Mao S, Liu J, Li S, Wang J. Reactive oxygen species involved in CT26 immunogenic cell death induced by Clostridium difficile toxin B. Immunol Lett (2015) 164(2):65–71. doi:10.1016/j.imlet.2015.02.007

PubMed Abstract | CrossRef Full Text | Google Scholar

150. Miyamoto S, Inoue H, Nakamura T, Yamada M, Sakamoto C, Urata Y, et al. Coxsackievirus B3 Is an oncolytic virus with immunostimulatory properties that is active against lung Adenocarcinoma. Cancer Res (2012) 72(10):2609–21. doi:10.1158/0008-5472.CAN-11-3185

PubMed Abstract | CrossRef Full Text | Google Scholar

151. Vacchelli E, Eggermont A, Sautes-Fridman C, Galon J, Zitvogel L, Kroemer G, et al. Trial watch: oncolytic viruses for cancer therapy. Oncoimmunology (2013) 2(6):e24612. doi:10.4161/onci.22789

PubMed Abstract | CrossRef Full Text | Google Scholar

152. Schiavoni G, Sistigu A, Valentini M, Mattei F, Sestili P, Spadaro F, et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res (2011) 71(3):768–78. doi:10.1158/0008-5472.CAN-10-2788

PubMed Abstract | CrossRef Full Text | Google Scholar

153. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science (2013) 342(6161):971–6. doi:10.1126/science.1240537

PubMed Abstract | CrossRef Full Text | Google Scholar

154. Fucikova J, Moserova I, Truxova I, Hermanova I, Vancurova I, Partlova S, et al. High hydrostatic pressure induces immunogenic cell death in human tumor cells. Int J Cancer (2014) 135(5):1165–77. doi:10.1002/ijc.28766

PubMed Abstract | CrossRef Full Text | Google Scholar

155. Adkins I, Fucikova J, Garg AD, Agostinis P, Spisek R. Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy. Oncoimmunology (2014) 3:e968434. doi:10.4161/21624011.2014.968434

PubMed Abstract | CrossRef Full Text | Google Scholar

156. Weiss EM, Meister S, Janko C, Ebel N, Schlucker E, Meyer-Pittroff R, et al. High hydrostatic pressure treatment generates inactivated mammalian tumor cells with immunogeneic features. J Immunotoxicol (2010) 7(3):194–204. doi:10.3109/15476911003657414

PubMed Abstract | CrossRef Full Text | Google Scholar

157. Garg AD, Agostinis P. ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses. Photochem Photobiol Sci (2014) 13(3):474–87. doi:10.1039/c3pp50333j

PubMed Abstract | CrossRef Full Text | Google Scholar

158. Yu Z, Geng J, Zhang M, Zhou Y, Fan Q, Chen J. Treatment of osteosarcoma with microwave thermal ablation to induce immunogenic cell death. Oncotarget (2014) 5(15):6526–39. doi:10.18632/oncotarget.2310

PubMed Abstract | CrossRef Full Text | Google Scholar

159. Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med (2014) 6(226):226ra32. doi:10.1126/scitranslmed.3008095

PubMed Abstract | CrossRef Full Text | Google Scholar

160. Chen HM, Wang PH, Chen SS, Wen CC, Chen YH, Yang WC, et al. Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine. Cancer Immunol Immunother (2012) 61(11):1989–2002. doi:10.1007/s00262-012-1258-9

PubMed Abstract | CrossRef Full Text | Google Scholar

161. Korbelik M, Dougherty GJ. Photodynamic therapy-mediated immune response against subcutaneous mouse tumors. Cancer Res (1999) 59(8):1941–6.

PubMed Abstract | Google Scholar

162. Krosl G, Korbelik M, Dougherty GJ. Induction of immune cell infiltration into murine SCCVII tumour by photofrin-based photodynamic therapy. Br J Cancer (1995) 71(3):549–55. doi:10.1038/bjc.1995.108

PubMed Abstract | CrossRef Full Text | Google Scholar

163. Korbelik M, Stott B, Sun J. Photodynamic therapy-generated vaccines: relevance of tumour cell death expression. Br J Cancer (2007) 97(10):1381–7. doi:10.1038/sj.bjc.6604059

PubMed Abstract | CrossRef Full Text | Google Scholar

164. Korbelik M, Zhang W, Merchant S. Involvement of damage-associated molecular patterns in tumor response to photodynamic therapy: surface expression of calreticulin and high-mobility group box-1 release. Cancer Immunol Immunother (2011) 60(10):1431–7. doi:10.1007/s00262-011-1047-x

PubMed Abstract | CrossRef Full Text | Google Scholar

165. Duewell P, Steger A, Lohr H, Bourhis H, Hoelz H, Kirchleitner SV, et al. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8 T cells. Cell Death Differ (2014) 21(12):1825–37. doi:10.1038/cdd.2014.96

PubMed Abstract | CrossRef Full Text | Google Scholar

166. West AC, Mattarollo SR, Shortt J, Cluse LA, Christiansen AJ, Smyth MJ, et al. An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Res (2013) 73(24):7265–76. doi:10.1158/0008-5472.CAN-13-0890

PubMed Abstract | CrossRef Full Text | Google Scholar

167. Yang Y, Li XJ, Chen Z, Zhu XX, Wang J, Zhang LB, et al. Wogonin induced calreticulin/annexin A1 exposure dictates the immunogenicity of cancer cells in a PERK/AKT dependent manner. PLoS One (2012) 7(12):e50811. doi:10.1371/journal.pone.0050811

PubMed Abstract | CrossRef Full Text | Google Scholar

168. Panzarini E, Inguscio V, Fimia GM, Dini L. Rose Bengal acetate photodynamic therapy (RBAc-PDT) induces exposure and release of damage-associated molecular patterns (DAMPs) in human HeLa cells. PLoS One (2014) 9(8):e105778. doi:10.1371/journal.pone.0105778

PubMed Abstract | CrossRef Full Text | Google Scholar

169. Molinari R, D’Eliseo D, Manzi L, Zolla L, Velotti F, Merendino N. The n3-polyunsaturated fatty acid docosahexaenoic acid induces immunogenic cell death in human cancer cell lines via pre-apoptotic calreticulin exposure. Cancer Immunol Immunother (2011) 60(10):1503–7. doi:10.1007/s00262-011-1074-7

PubMed Abstract | CrossRef Full Text | Google Scholar

170. D’Eliseo D, Manzi L, Velotti F. Capsaicin as an inducer of damage-associated molecular patterns (DAMPs) of immunogenic cell death (ICD) in human bladder cancer cells. Cell Stress Chaperones (2013) 18(6):801–8. doi:10.1007/s12192-013-0422-2

PubMed Abstract | CrossRef Full Text | Google Scholar

171. Gilardini Montani MS, D’Eliseo D, Cirone M, Di Renzo L, Faggioni A, Santoni A, et al. Capsaicin-mediated apoptosis of human bladder cancer cells activates dendritic cells via CD91. Nutrition (2015) 31(4):578–81. doi:10.1016/j.nut.2014.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

172. Janeway C. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science (2005). 823 p.

Google Scholar

173. Fucikova J, Kralikova P, Fialova A, Brtnicky T, Rob L, Bartunkova J, et al. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res (2011) 71(14):4821–33. doi:10.1158/0008-5472.CAN-11-0950

PubMed Abstract | CrossRef Full Text | Google Scholar

174. Krysko DV, Kaczmarek A, Krysko O, Heyndrickx L, Woznicki J, Bogaert P, et al. TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. Cell Death Differ (2011) 18(8):1316–25. doi:10.1038/cdd.2011.4

PubMed Abstract | CrossRef Full Text | Google Scholar

175. Tseng LM, Liu CY, Chang KC, Chu PY, Shiau CW, Chen KF. CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res (2012) 14(2):R68. doi:10.1186/bcr3175

PubMed Abstract | CrossRef Full Text | Google Scholar

176. Davies AM, Lara PN Jr, Mack PC, Gandara DR. Incorporating bortezomib into the treatment of lung cancer. Clin Cancer Res (2007) 13(15 Pt 2):s4647–51. doi:10.1158/1078-0432.CCR-07-0334

PubMed Abstract | CrossRef Full Text | Google Scholar

177. Huang T, Li S, Li G, Tian Y, Wang H, Shi L, et al. Utility of Clostridium difficile toxin B for inducing anti-tumor immunity. PLoS One (2014) 9(10):e110826. doi:10.1371/journal.pone.0110826

PubMed Abstract | CrossRef Full Text | Google Scholar

178. Bravim F, de Freitas JM, Fernandes AA, Fernandes PM. High hydrostatic pressure and the cell membrane: stress response of Saccharomyces cerevisiae. Ann N Y Acad Sci (2010) 1189:127–32. doi:10.1111/j.1749-6632.2009.05182.x

PubMed Abstract | CrossRef Full Text | Google Scholar

179. Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M, et al. An immunosurveillance mechanism controls cancer cell ploidy. Science (2012) 337(6102):1678–84. doi:10.1126/science.1224922

PubMed Abstract | CrossRef Full Text | Google Scholar

180. Korbelik M. Cancer vaccines generated by photodynamic therapy. Photochem Photobiol Sci (2011) 10(5):664–9. doi:10.1039/c0pp00343c

PubMed Abstract | CrossRef Full Text | Google Scholar

181. Garg AD, Krysko DV, Vandenabeele P, Agostinis P. DAMPs and PDT-mediated photo-oxidative stress: exploring the unknown. Photochem Photobiol Sci (2011) 10(5):670–80. doi:10.1039/c0pp00294a

PubMed Abstract | CrossRef Full Text | Google Scholar

182. Chen J, Xie J, Jiang Z, Wang B, Wang Y, Hu X. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene (2011) 30(42):4297–306. doi:10.1038/onc.2011.137

PubMed Abstract | CrossRef Full Text | Google Scholar

183. Tsai CF, Yeh WL, Huang SM, Tan TW, Lu DY. Wogonin induces reactive oxygen species production and cell apoptosis in human glioma cancer cells. Int J Mol Sci (2012) 13(8):9877–92. doi:10.3390/ijms13089877

PubMed Abstract | CrossRef Full Text | Google Scholar

184. Sanovic R, Verwanger T, Hartl A, Krammer B. Low dose hypericin-PDT induces complete tumor regression in BALB/c mice bearing CT26 colon carcinoma. Photodiagnosis Photodyn Ther (2011) 8(4):291–6. doi:10.1016/j.pdpdt.2011.04.003

PubMed Abstract | CrossRef Full Text | Google Scholar

185. Garg AD, Krysko DV, Vandenabeele P, Agostinis P. The emergence of phox-ER stress induced immunogenic apoptosis. OncoImmunology (2012) 1(5):787–9. doi:10.4161/onci.19750

PubMed Abstract | CrossRef Full Text | Google Scholar

186. Liu Z, Zhang HM, Yuan J, Ye X, Taylor GA, Yang D. The immunity-related GTPase Irgm3 relieves endoplasmic reticulum stress response during Coxsackievirus B3 infection via a PI3K/Akt dependent pathway. Cell Microbiol (2012) 14(1):133–46. doi:10.1111/j.1462-5822.2011.01708.x

PubMed Abstract | CrossRef Full Text | Google Scholar

187. Bian J, Wang K, Kong X, Liu H, Chen F, Hu M, et al. Caspase- and p38-MAPK-dependent induction of apoptosis in A549 lung cancer cells by Newcastle disease virus. Arch Virol (2011) 156(8):1335–44. doi:10.1007/s00705-011-0987-y

PubMed Abstract | CrossRef Full Text | Google Scholar

188. Garg AD, De Ruysscher D, Agostinis P. Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: a large-scale meta-analysis. Oncoimmunology (2015). doi:10.1080/2162402X.2015.1069938

CrossRef Full Text | Google Scholar

189. Galluzzi L, Kepp O, Kroemer G. Enlightening the impact of immunogenic cell death in photodynamic cancer therapy. EMBO J (2012) 31(5):1055–7. doi:10.1038/emboj.2012.2

CrossRef Full Text | Google Scholar

190. Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, et al. Autophagy in malignant transformation and cancer progression. EMBO J (2015) 34(7):856–80. doi:10.15252/embj.201490784

PubMed Abstract | CrossRef Full Text | Google Scholar

191. Mattarollo SR, Loi S, Duret H, Ma Y, Zitvogel L, Smyth MJ. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res (2011) 71(14):4809–20. doi:10.1158/0008-5472.CAN-11-0753

PubMed Abstract | CrossRef Full Text | Google Scholar

192. Lin TJ, Lin HT, Chang WT, Mitapalli SP, Hsiao PW, Yin SY, et al. Shikonin-enhanced cell immunogenicity of tumor vaccine is mediated by the differential effects of DAMP components. Mol Cancer (2015) 14:174. doi:10.1186/s12943-015-0435-9

PubMed Abstract | CrossRef Full Text | Google Scholar

193. Ma Y, Aymeric L, Locher C, Mattarollo SR, Delahaye NF, Pereira P, et al. Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J Exp Med (2011) 208(3):491–503. doi:10.1084/jem.20100269

PubMed Abstract | CrossRef Full Text | Google Scholar

194. Yang H, Yamazaki T, Pietrocola F, Zhou H, Zitvogel L, Ma Y, et al. STAT3 inhibition enhances the therapeutic efficacy of immunogenic chemotherapy by stimulating type 1 interferon production by cancer cells. Cancer Res (2015) 75(18):3812–22. doi:10.1158/0008-5472.CAN-15-1122

PubMed Abstract | CrossRef Full Text | Google Scholar

195. Ciampricotti M, Hau CS, Doornebal CW, Jonkers J, de Visser KE. Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nat Med (2012) 18(3):344–6. doi:10.1038/nm.2652

CrossRef Full Text | Google Scholar

196. Gould SE, Junttila MR, de Sauvage FJ. Translational value of mouse models in oncology drug development. Nat Med (2015) 21(5):431–9. doi:10.1038/nm.3853

PubMed Abstract | CrossRef Full Text | Google Scholar

197. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene (2010) 29(4):482–91. doi:10.1038/onc.2009.356

PubMed Abstract | CrossRef Full Text | Google Scholar

198. Hannesdottir L, Tymoszuk P, Parajuli N, Wasmer MH, Philipp S, Daschil N, et al. Lapatinib and doxorubicin enhance the Stat1-dependent antitumor immune response. Eur J Immunol (2013) 43(10):2718–29. doi:10.1002/eji.201242505

PubMed Abstract | CrossRef Full Text | Google Scholar

199. Michaud M, Xie X, Bravo-San Pedro JM, Zitvogel L, White E, Kroemer G. An autophagy-dependent anticancer immune response determines the efficacy of melanoma chemotherapy. Oncoimmunology (2014) 3(7):e944047. doi:10.4161/21624011.2014.944047

PubMed Abstract | CrossRef Full Text | Google Scholar

200. Demaria S, Santori FR, Ng B, Liebes L, Formenti SC, Vukmanovic S. Select forms of tumor cell apoptosis induce dendritic cell maturation. J Leukoc Biol (2005) 77(3):361–8. doi:10.1189/jlb.0804478

PubMed Abstract | CrossRef Full Text | Google Scholar

201. Schumacher LY, Vo DD, Garban HJ, Comin-Anduix B, Owens SK, Dissette VB, et al. Immunosensitization of tumor cells to dendritic cell-activated immune responses with the proteasome inhibitor bortezomib (PS-341, Velcade). J Immunol (2006) 176(8):4757–65. doi:10.4049/​jimmunol.176.8.4757

PubMed Abstract | CrossRef Full Text | Google Scholar

202. Chang CL, Hsu YT, Wu CC, Yang YC, Wang C, Wu TC, et al. Immune mechanism of the antitumor effects generated by bortezomib. J Immunol (2012) 189(6):3209–20. doi:10.4049/jimmunol.1103826

PubMed Abstract | CrossRef Full Text | Google Scholar

203. van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, et al. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother (2009) 58(8):1219–28. doi:10.1007/s00262-008-0628-9

PubMed Abstract | CrossRef Full Text | Google Scholar

204. Obeid M, Panaretakis T, Joza N, Tufi R, Tesniere A, van Endert P, et al. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ (2007) 14(10):1848–50. doi:10.1038/sj.cdd.4402201

CrossRef Full Text | Google Scholar

205. Carr-Brendel V, Markovic D, Smith M, Taylor-Papadimitriou J, Cohen EP. Immunity to breast cancer in mice immunized with X-irradiated breast cancer cells modified to secrete IL-12. J Immunother (1999) 22(5):415–22. doi:10.1097/00002371-199909000-00005

PubMed Abstract | CrossRef Full Text | Google Scholar

206. Strome SE, Voss S, Wilcox R, Wakefield TL, Tamada K, Flies D, et al. Strategies for antigen loading of dendritic cells to enhance the antitumor immune response. Cancer Res (2002) 62(6):1884–9.

PubMed Abstract | Google Scholar

207. Prasad SJ, Farrand KJ, Matthews SA, Chang JH, McHugh RS, Ronchese F. Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+ regulatory T cells. J Immunol (2005) 174(1):90–8. doi:10.4049/jimmunol.174.1.90

PubMed Abstract | CrossRef Full Text | Google Scholar

208. Yang H, Zhou P, Huang H, Chen D, Ma N, Cui QC, et al. Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. Int J Cancer (2009) 124(10):2450–9. doi:10.1002/ijc.24195

PubMed Abstract | CrossRef Full Text | Google Scholar

209. Sharma P, Allison JP. The future of immune checkpoint therapy. Science (2015) 348(6230):56–61. doi:10.1126/science.aaa8172

PubMed Abstract | CrossRef Full Text | Google Scholar

210. Viney M, Lazarou L, Abolins S. The laboratory mouse and wild immunology. Parasite Immunol (2015) 37(5):267–73. doi:10.1111/pim.12150

PubMed Abstract | CrossRef Full Text | Google Scholar

211. Davis MM. A prescription for human immunology. Immunity (2008) 29(6):835–8. doi:10.1016/j.immuni.2008.12.003

PubMed Abstract | CrossRef Full Text | Google Scholar

212. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol (2004) 172(5):2731–8. doi:10.4049/jimmunol.172.5.2731

PubMed Abstract | CrossRef Full Text | Google Scholar

213. Tubiana M. Klaas Breur medal lecture 1985. The growth and progression of human tumors: implications for management strategy. Radiother Oncol (1986) 6(3):167–84. doi:10.1016/S0167-8140(86)80151-7

PubMed Abstract | CrossRef Full Text | Google Scholar

214. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer (2009) 9(4):302–12. doi:10.1038/nrc2627

PubMed Abstract | CrossRef Full Text | Google Scholar

215. Yamazaki T, Hannani D, Poirier-Colame V, Ladoire S, Locher C, Sistigu A, et al. Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. Cell Death Differ (2014) 21(1):69–78. doi:10.1038/cdd.2013.72

PubMed Abstract | CrossRef Full Text | Google Scholar

216. Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ, et al. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci U S A (2013) 110(27):11091–6. doi:10.1073/pnas.1222251110

PubMed Abstract | CrossRef Full Text | Google Scholar

217. Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D, et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature (2015) 521(7550):94–8. doi:10.1038/nature14395

PubMed Abstract | CrossRef Full Text | Google Scholar

218. De Boo S, Kopecka J, Brusa D, Gazzano E, Matera L, Ghigo D, et al. iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells. Mol Cancer (2009) 8:108. doi:10.1186/1476-4598-8-108

PubMed Abstract | CrossRef Full Text | Google Scholar

219. Riganti C, Castella B, Kopecka J, Campia I, Coscia M, Pescarmona G, et al. Zoledronic acid restores doxorubicin chemosensitivity and immunogenic cell death in multidrug-resistant human cancer cells. PLoS One (2013) 8(4):e60975. doi:10.1371/journal.pone.0060975

PubMed Abstract | CrossRef Full Text | Google Scholar

220. Stoll G, Enot D, Mlecnik B, Galon J, Zitvogel L, Kroemer G. Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy. Oncoimmunology (2014) 3(1):e27884. doi:10.4161/onci.27884

PubMed Abstract | CrossRef Full Text | Google Scholar

221. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer (2012) 12(4):252–64. doi:10.1038/nrc3239

PubMed Abstract | CrossRef Full Text | Google Scholar

222. Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity (2013) 39(1):11–26. doi:10.1016/j.immuni.2013.07.008

PubMed Abstract | CrossRef Full Text | Google Scholar

223. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer (2012) 12(4):298–306. doi:10.1038/nrc3245

PubMed Abstract | CrossRef Full Text | Google Scholar

224. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol (2006) 6(10):715–27. doi:10.1038/nri1936

PubMed Abstract | CrossRef Full Text | Google Scholar

225. Ladoire S, Penault-Llorca F, Senovilla L, Dalban C, Enot D, Locher C, et al. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer. Autophagy (2015) 11(10):1878–90. doi:10.1080/15548627.2015.1082022

PubMed Abstract | CrossRef Full Text | Google Scholar

226. Kacerovska D, Pizinger K, Majer F, Smid F. Photodynamic therapy of nonmelanoma skin cancer with topical Hypericum perforatum extract – a pilot study. Photochem Photobiol (2008) 84(3):779–85. doi:10.1111/j.1751-1097.2007.00260.x

PubMed Abstract | CrossRef Full Text | Google Scholar

227. Rook AH, Wood GS, Duvic M, Vonderheid EC, Tobia A, Cabana B. A phase II placebo-controlled study of photodynamic therapy with topical hypericin and visible light irradiation in the treatment of cutaneous T-cell lymphoma and psoriasis. J Am Acad Dermatol (2010) 63(6):984–90. doi:10.1016/j.jaad.2010.02.039

PubMed Abstract | CrossRef Full Text | Google Scholar

228. Koren H, Schenk GM, Jindra RH, Alth G, Ebermann R, Kubin A, et al. Hypericin in phototherapy. J Photochem Photobiol B (1996) 36(2):113–9. doi:10.1016/S1011-1344(96)07357-5

PubMed Abstract | CrossRef Full Text | Google Scholar

229. Alecu M, Ursaciuc C, Halalau F, Coman G, Merlevede W, Waelkens E, et al. Photodynamic treatment of basal cell carcinoma and squamous cell carcinoma with hypericin. Anticancer Res (1998) 18(6B):4651–4.

PubMed Abstract | Google Scholar

230. Liikanen I, Koski A, Merisalo-Soikkeli M, Hemminki O, Oksanen M, Kairemo K, et al. Serum HMGB1 is a predictive and prognostic biomarker for oncolytic immunotherapy. Oncoimmunology (2015) 4(3):e989771. doi:10.4161/2162402X.2014.989771

PubMed Abstract | CrossRef Full Text | Google Scholar

231. Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, et al. Photodynamic therapy of cancer: an update. CA Cancer J Clin (2011) 61(4):250–81. doi:10.3322/caac.20114

PubMed Abstract | CrossRef Full Text | Google Scholar

232. Suzuki Y, Mimura K, Yoshimoto Y, Watanabe M, Ohkubo Y, Izawa S, et al. Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Res (2012) 72(16):3967–76. doi:10.1158/0008-5472.CAN-12-0851

PubMed Abstract | CrossRef Full Text | Google Scholar

233. Zappasodi R, Pupa SM, Ghedini GC, Bongarzone I, Magni M, Cabras AD, et al. Improved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death. Cancer Res (2010) 70(22):9062–72. doi:10.1158/0008-5472.CAN-10-1825

PubMed Abstract | CrossRef Full Text | Google Scholar

234. Baitsch L, Fuertes-Marraco SA, Legat A, Meyer C, Speiser DE. The three main stumbling blocks for anticancer T cells. Trends Immunol (2012) 33(7):364–72. doi:10.1016/j.it.2012.02.006

PubMed Abstract | CrossRef Full Text | Google Scholar

235. Redmond WL, Sherman LA. Peripheral tolerance of CD8 T lymphocytes. Immunity (2005) 22(3):275–84. doi:10.1016/j.immuni.2005.01.010

PubMed Abstract | CrossRef Full Text | Google Scholar

236. Cole DK, Pumphrey NJ, Boulter JM, Sami M, Bell JI, Gostick E, et al. Human TCR-binding affinity is governed by MHC class restriction. J Immunol (2007) 178(9):5727–34. doi:10.4049/jimmunol.178.9.5727

PubMed Abstract | CrossRef Full Text | Google Scholar

237. Schmid DA, Irving MB, Posevitz V, Hebeisen M, Posevitz-Fejfar A, Sarria JC, et al. Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol (2010) 184(9):4936–46. doi:10.4049/jimmunol.1000173

PubMed Abstract | CrossRef Full Text | Google Scholar

238. Zehn D, Bevan MJ. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity (2006) 25(2):261–70. doi:10.1016/j.immuni.2006.06.009

PubMed Abstract | CrossRef Full Text | Google Scholar

239. Baumgaertner P, Jandus C, Rivals JP, Derre L, Lovgren T, Baitsch L, et al. Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer (2012) 130(11):2607–17. doi:10.1002/ijc.26297

PubMed Abstract | CrossRef Full Text | Google Scholar

240. Gubin MM, Artyomov MN, Mardis ER, Schreiber RD. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest (2015) 125(9):3413–21. doi:10.1172/JCI80008

PubMed Abstract | CrossRef Full Text | Google Scholar

241. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science (2015) 348(6230):69–74. doi:10.1126/science.aaa4971

PubMed Abstract | CrossRef Full Text | Google Scholar

242. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature (2015) 520(7547):373–7. doi:10.1038/nature14292

PubMed Abstract | CrossRef Full Text | Google Scholar

243. Ochsenbein AF, Klenerman P, Karrer U, Ludewig B, Pericin M, Hengartner H, et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci U S A (1999) 96(5):2233–8. doi:10.1073/pnas.96.5.2233

PubMed Abstract | CrossRef Full Text | Google Scholar

244. Chu-Yuan H, Jing P, Yi-Sheng W, He-Ping P, Hui Y, Chu-Xiong Z, et al. The impact of chemotherapy-associated neutrophil/lymphocyte counts on prognosis of adjuvant chemotherapy in colorectal cancer. BMC Cancer (2013) 13:177. doi:10.1186/1471-2407-13-177

PubMed Abstract | CrossRef Full Text | Google Scholar

245. Inoges S, Rodriguez-Calvillo M, Zabalegui N, Lopez-Diaz de Cerio A, Villanueva H, Soria E, et al. Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. J Natl Cancer Inst (2006) 98(18):1292–301. doi:10.1093/jnci/djj358

PubMed Abstract | CrossRef Full Text | Google Scholar

246. Kakarla S, Gottschalk S. CAR T cells for solid tumors: armed and ready to go? Cancer J (2014) 20(2):151–5. doi:10.1097/PPO.0000000000000032

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: anti-tumor immunity, immunogenicity, immunotherapy, molecular medicine, oncoimmunology, patient prognosis, translational medicine

Citation: Garg AD, Galluzzi L, Apetoh L, Baert T, Birge RB, Bravo-San Pedro JM, Breckpot K, Brough D, Chaurio R, Cirone M, Coosemans A, Coulie PG, De Ruysscher D, Dini L, de Witte P, Dudek-Peric AM, Faggioni A, Fucikova J, Gaipl US, Golab J, Gougeon M-L, Hamblin MR, Hemminki A, Herrmann M, Hodge JW, Kepp O, Kroemer G, Krysko DV, Land WG, Madeo F, Manfredi AA, Mattarollo SR, Maueroder C, Merendino N, Multhoff G, Pabst T, Ricci J-E, Riganti C, Romano E, Rufo N, Smyth MJ, Sonnemann J, Spisek R, Stagg J, Vacchelli E, Vandenabeele P, Vandenberk L, Van den Eynde BJ, Van Gool S, Velotti F, Zitvogel L and Agostinis P (2015) Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death. Front. Immunol. 6:588. doi: 10.3389/fimmu.2015.00588

Received: 17 September 2015; Accepted: 02 November 2015;
Published: 20 November 2015

Edited by:

Fabrizio Mattei, Istituto Superiore di Sanità, Italy

Reviewed by:

Luis De La Cruz-Merino, Hospital Universitario Virgen Macarena, Spain
Carlos Alfaro, Clínica Universidad de Navarra, Spain

Copyright: © 2015 Garg, Galluzzi, Apetoh, Baert, Birge, Bravo-San Pedro, Breckpot, Brough, Chaurio, Cirone, Coosemans, Coulie, De Ruysscher, Dini, de Witte, Dudek-Peric, Faggioni, Fucikova, Gaipl, Golab, Gougeon, Hamblin, Hemminki, Herrmann, Hodge, Kepp, Kroemer, Krysko, Land, Madeo, Manfredi, Mattarollo, Maueroder, Merendino, Multhoff, Pabst, Ricci, Riganti, Romano, Rufo, Smyth, Sonnemann, Spisek, Stagg, Vacchelli, Vandenabeele, Vandenberk, Van den Eynde, Van Gool, Velotti, Zitvogel and Agostinis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Abhishek D. Garg, abhishek.garg@med.kuleuven.be, abhishekdgarg@gmail.com;
Patrizia Agostinis, patrizia.agostinis@med.kuleuven.be