AUTHOR=Campbell Colin , Zhang Ranran , Haley Jeremy S., Liu Xin , Loughran Thomas , Schell Todd , Albert Reka , Thakar Juilee 

TITLE=Why Do CD8+ T Cells become Indifferent to Tumors: A Dynamic Modeling Approach

JOURNAL=Frontiers in Physiology

VOLUME=2

YEAR=2011

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2011.00032

DOI=10.3389/fphys.2011.00032

ISSN=1664-042X

ABSTRACT=<p>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 (<italic>H-2<sup>b</sup></italic>) mice. To understand the <italic>in vivo</italic> quantitative dynamics of CD8+ T cells after encountering Tag, we constructed a dynamic model from <italic>in vivo</italic>-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.</p>