Why do CD8+T cells become indifferent to tumors: A dynamic modeling approach

D8+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 largeT-antigen (Tag) oncoprotein promotes tumor formation inTag-transgenic mice and also provides multiple target determinants (sites) for responding CD8+ T cells in C57BL/6 (H-2 ^b) 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-specificT 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.