%A Campbell,Colin %A Zhang,Ranran %A Haley,Jeremy %A Liu,Xin %A Loughran,Thomas %A Schell,Todd %A Albert,Reka %A Thakar,Juilee %D 2011 %J Frontiers in Physiology %C %F %G English %K apoptosis and proliferation rates,CD8+ T cells,dynamic model,T-antigen,tumor %Q %R 10.3389/fphys.2011.00032 %W %L %M %P %7 %8 2011-July-11 %9 Original Research %+ Dr Juilee Thakar,Yale University,Pathology,300 George Street,,Suite 505,New Haven,06511,Connecticut,United States,Juilee_Thakar@urmc.rochester.edu %# %! Quantitative study of tumor pathogenesis %* %< %T Why Do CD8+ T Cells become Indifferent to Tumors: A Dynamic Modeling Approach %U https://www.frontiersin.org/articles/10.3389/fphys.2011.00032 %V 2 %0 JOURNAL ARTICLE %@ 1664-042X %X CD8+ T cells have the potential to influence the outcome of cancer pathogenesis, including complete tumor eradication or selection of malignant tumor escape variants. The Simian virus 40 large T-antigen (Tag) oncoprotein promotes tumor formation in Tag-transgenic mice and also provides multiple target determinants (sites) for responding CD8+ T cells in C57BL/6 (H-2b) mice. To understand the in vivo quantitative dynamics of CD8+ T cells after encountering Tag, we constructed a dynamic model from in vivo-generated data to simulate the interactions between Tag-expressing cells and CD8+ T cells in distinct scenarios including immunization of wild-type C57BL/6 mice and of Tag-transgenic mice that develop various tumors. In these scenarios the model successfully reproduces the dynamics of both the Tag-expressing cells and antigen-specific CD8+ T cell responses. The model predicts that the tolerance of the site-specific T cells is dependent on their apoptosis rates and that the net growth of CD8+ T cells is altered in transgenic mice. We experimentally validate both predictions. Our results indicate that site-specific CD8+ T cells have tissue-specific apoptosis rates affecting their tolerance to the tumor antigen. Moreover, the model highlights differences in apoptosis rates that contribute to compromised CD8+ T cell responses and tumor progression, knowledge of which is essential for development of cancer immunotherapy.