Modeling the Development of Cellular Exhaustion and Tumor-Immune Stalemate

Cellular exhaustion in various immune cells develops in response to prolonged stimulation and overactivation during chronic infections and in cancer. Marked by an upregulation of inhibitory receptors and diminished effector functions, exhausted immune cells are unable to fully eradicate the antigen responsible for the overexposure. In cancer settings, this results in a relatively small but constant tumor burden known as a localized tumor-immune stalemate. In recent years, studies have elucidated key aspects of the development and progression of cellular exhaustion and have re-addressed previous misconceptions. Biological publications have also provided insight into the functional capabilities of exhausted cells. Complementing these findings, the model presented here serves as a mathematical framework for the establishment of cellular exhaustion and the development of the localized stalemate against a solid tumor. Analysis of this model indicates that this stalemate is stable and can handle small perturbations. Additionally, model analysis also provides insight into potential targets of future immunotherapy efforts.