title: Why Do CD8+ T Cells become Indifferent to Tumors: A Dynamic Modeling Approach.
abstract: 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-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-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.
authors.affiliation: Department of Physics, The Pennsylvania State University University Park, PA, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Campbell
authors.forename: Ranran
authors.initials: R
authors.lastname: Zhang
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Haley
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Loughran
authors.forename: Todd D
authors.initials: TD
authors.lastname: Schell
authors.forename: Réka
authors.initials: R
authors.lastname: Albert
authors.forename: Juilee
authors.initials: J
authors.lastname: Thakar