María Marcela Barrio
Estrella Mariel Levy
José Mordoh- 1Fundación Cáncer FUCA, Centro de Investigaciones Oncológicas, Buenos Aires, Argentina
- 2Fundación Instituto Leloir, Buenos Aires, Argentina
- 3Instituto Alexander Fleming, Buenos Aires, Argentina
Cancer immunotherapy has recently emerged as the fourth treatment modality, in addition to surgery, chemotherapy, and radiotherapy. These advances are the result of important discoveries in the field of regulation of the immune response, especially on the mechanisms which turn “on” and “off” immune responses (1, 2). A disease which has proved to be a canonical model to test therapeutic immunotherapy is the immunogenic cutaneous melanoma (3). So far, “passive” immunotherapy with monoclonal antibodies has outpaced “active” immunotherapy with antitumor vaccines (4, 5), and monoclonal antibodies which antagonize the “off” responses have been recently introduced in clinical practice (6, 7).
In this Research Topic containing nine articles, Aris and Barrio (8) present an updated review of current immunotherapeutic strategies and their combinations with oncogene-targeted therapy for cutaneous melanoma. Preclinical evidence, as well as emerging clinical results outlined in this review, might represent potentially powerful tools for cancer treatment. Besides, several monoclonal antibodies have been introduced into the clinic for cancer treatment. Among them, recently arrived anti-chemokine receptor antibodies are presented in a review by Vela et al. (9). The authors discuss the main achievements obtained with them to inhibit the interactions between cancer cells and their ligands. These antibodies hinder the interactions between chemokine receptors and chemokine signals delivered by different organs, thus preventing tumor cell survival, proliferation, adhesion, or migration that could result in metastatic spreading.
In spite of these recent successes, many unresolved practical and theoretical clues remain to be answered. The review by Madorsky Rowdo et al. (10) addresses relevant questions about the identity of the lymphocytes that eliminate tumor cells, their entry into tumor microenvironment, and parameters that could be used to determine the anti-tumor immune response. Also, the use of cancer vaccines to increase the lymphocytic tumor infiltration and the multiplicity of antigens that must be targeted to achieve significant clinical responses are discussed. Related to this issue, a Clinical Case Study reported by Aris et al. (11) shows histological evidence of the recruitment of immune cells induced by an anti-melanoma vaccine at the inoculation site, probably reflecting the early steps of the afferent immune response. Moreover, antitumor vaccination has been extensively developed in the last 15 years, even to target immune responses to hematologic tumors. Here, Di Stasi et al. (12) present the results obtained in the clinic with a peptide vaccination strategy that targets WT1 antigen in acute myeloid leukemia and myelodysplastic syndromes. Evidence of WT1-specific T cells induction that correlates with progression-free survival has been shown in several studies, encouraging further investigation to strengthen this cancer vaccination approach.
Regarding the development of adaptive antitumor immune responses, a basic assumption was that infiltrating anti-tumor immune cells were educated to recognize tumor antigens in secondary lymphoid organs, and were then recruited into the tumor microenvironment to exert anti-tumor activity. Here, Germain et al. (13) present evidence, focusing on the B cell compartment, suggesting that the immune response can also take place in tertiary lymphoid structures located in the areas of chronic inflammation as well as in cancer.
Dendritic cells (DC) play a pivotal role on the orchestration of the immune responses and are thus key targets in cancer vaccine design. In this Research Topic, three reviews address the role of DC in immunotherapy. First, recent findings in murine models regarding the anti-tumoral mechanisms of DC-based vaccination are reviewed by Mac Keon et al. (14). They focus on diverse issues, such as the antigen sources, the use of adjuvants, DC maturing agents, and the role of DC subsets in the antitumor response. In the human setting, Pizzurro and Barrio (15) present the main hot spots of the anti-tumor immune response, which are exploited with different DC-based vaccine designs. They focus on the processes taking place at the injection site, new adjuvants combinations, as well as lymph nodes homing to activate naïve lymphocytes and generating effector cells, and immune memory to control tumor growth. Finally, Pampena and Levy (16) discuss the participation of natural killer (NK) cells as alternative immune components that could cooperate in successful vaccination treatment. This article addresses the NK cell antitumor action sites and their role in DC-based cancer vaccines as determined by immune-monitoring in preclinical and clinical settings.
With no doubt, cancer immunotherapy is now a treatment modality that can change the reality for many cancer patients, achieving prolongation of their metastasis-free and overall survival. Scientific research over the last 20 years supports a key role of the immune system in the elimination of the disease, opening new roads for combinatorial treatments to be tested in the clinic. The contributions included in this Research Topic have exposed current lines of investigation, where clinical successes are recognized, but also a considerable lack of understanding of the mechanisms underlying such outcomes is also perceived. More research in the field is warranted to fully exploit the immune system as a therapeutic powerful tool for cancer patients.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science (1996) 271:1734–6. doi: 10.1126/science.271.5256.1734
2. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med (2002) 8:793–800. doi:10.1038/nm0902-1039c
3. Aris M, Barrio MM, Mordoh J. Lessons from cancer immunoediting in cutaneous melanoma. Clin Dev Immunol (2012) 2012:192719. doi:10.1155/2012/192719
4. Barrio MM, de Motta PT, Kaplan J, von Euw EM, Bravo AI, Chacón RD, et al. A phase I study of an allogeneic cell vaccine (VACCIMEL) with GM-CSF in melanoma patients. J Immunother (2006) 29:444–54. doi:10.1097/01.cji.0000208258.79005.5f
5. Beer TM, Bernstein GT, Corman JM, Glode LM, Hall SJ, Poll WL, et al. Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent 974 prostate cancer. Clin Cancer Res (2011) 17:4558–67. doi:10.1158/1078-0432.CCR-10-3223
6. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med (2010) 363:711–23. doi:10.1056/NEJMoa10034666
7. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet (2014) 6736:1–9.859. doi:10.1016/S0140-6736(14)60958-2
8. Aris M, Barrio MM. Combining immunotherapy with oncogene-targeted therapy: a new road for melanoma treatment. Front Immunol (2015) 6:46. doi:10.3389/fimmu.2015.00046
9. Vela M, Aris M, Llorente M, Garcia-Sanz JA, Kremer L. Chemokine receptor-specific antibodies in cancer immunotherapy: achievements and challenges. Front Immunol (2015) 6:12. doi:10.3389/fimmu.2015.00012
10. Madorsky Rowdo FP, Baron A, Urrutia M, Mordoh J. Immunotherapy in cancer: a combat between tumors and the immune system; you win some, you lose some. Front Immunol (2015) 6:127. doi:10.3389/fimmu.2015.00127
11. Aris M, Bravo AI, Barrio MM, Mordoh J. Inoculation site from a cutaneous melanoma patient treated with an allogeneic therapeutic vaccine: a case report. Front Immunol (2015) 6:144. doi:10.3389/fimmu.2015.00144
12. Di Stasi A, Jimenez AM, Minagawa K, Al-Obaidi M, Rezvani K. Review of the results of WT1 peptide vaccination strategies for myelodysplastic syndromes and acute myeloid leukemia from nine different studies. Front Immunol (2015) 6:36. doi:10.3389/fimmu.2015.00036
13. Germain C, Gnjatic S, Dieu-Nosjean MC. Tertiary lymphoid structure-associated B cells are key players in anti-tumor immunity. Front Immunol (2015) 6:67. doi:10.3389/fimmu.2015.00067
14. Mac Keon S, Ruiz MS, Gazzaniga S, Wainstok R. Dendritic cell-based vaccination in cancer: therapeutic implications emerging from murine models. Front Immunol (2015) 6:243. doi:10.3389/fimmu.2015.00243
15. Pizzurro GA, Barrio MM. Dendritic cell-based vaccine efficacy: aiming for hot spots. Front Immunol (2015) 6:91. doi:10.3389/fimmu.2015.00091
Keywords: cancer immunotherapy, immune checkpoint blockade, melanoma, mouse models, vaccines
Citation: Barrio MM, Levy EM and Mordoh J (2015) Editorial: “Cancer immunotherapy: lights and shadows”. Front. Immunol. 6:350. doi: 10.3389/fimmu.2015.00350
Received: 05 June 2015; Accepted: 24 June 2015;
Published: 07 July 2015
Edited and reviewed by: Kendall Arthur Smith, Weill Medical College of Cornell University, USA
Copyright: © 2015 Barrio, Levy and Mordoh. 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: José Mordoh, jmordoh@leloir.org.ar