Modeling the effect of hypoxic conditions on the IFNg secretion by adoptively transferred T cells

Abstract

Modeling the effect of hypoxic conditions on the IFNg secretion by adoptively transferred T cells Adoptive cell therapy (ACT) with tumor-infiltrating T lymphocytes (TIL) is transfusion of T cells derived from patients’ biopsies after enhancing their function in vitro. It is currently in clinical trials for several tumor types, including melanoma, one of the most immunogenic cancer types. However, the effectiveness of TIL adoptive therapy in melanomas could still be improved. We used mathematical modeling based on experimental data in order to test different ways to increase effectiveness of TIL therapy. We developed a spatial model of a melanoma tumor environment in mice, and used it to monitor the in silico tumor for up to 7 days after T cell transfer. Our focus was on characterizing the distribution of the proinflammatory cytokine interferon gamma (IFNg) which is secreted by the adoptively transferred T cells. In this model we varied three biologically controllable parameters: T cell number, T cell velocity and T cell phenotype (high IFNg producing or low IFNg -producing). We found that increasing the speed of T cells did not result in a more favourable IFNg distribution. We also found that high IFNg-producing T cell phenotype gave rise to a more favourable distribution than doubling the number of low IFNg-producing T cells. Overall, such mathematical modeling can generate new hypotheses for improving TIL therapy that can be subsequently tested in laboratory experiments.