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Item Mathematical Modeling of Cellular Exhaustion to Guide Future Immunotherapy Research(2024) Simmons, Tyler; Levy, Doron; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cellular exhaustion is a dysfunction found in various adaptive immune cells. In chronic settings, like cancer, antigen persistence and prolonged stimulation initiates the development of T cell exhaustion. The exhausted T cell population is a distinct lineage consisting of progenitor exhausted CD8+ T cells and terminally exhausted CD8+ T cells and is characterized by an upregulation of inhibitory receptor frequencies and diminished effector functions. The hypofunctionality of exhausted T cells prevents proper immunity and fails to eradicate the tumor. Recent years have shown a growing interest in targeting T cell exhaustion, attempting to reinvigorate effector functions, as a form of immunotherapy. Though beneficial responses have been reported in clinical settings, patient responses are inconsistent. Complementing the current biological understanding of T cell exhaustion and to advance immunotherapeutic efforts, novel research using mathematical modeling offers valuable insight. Constructing a foundational framework of an exhausted immune response to cancer provides an alternative approach to understanding the tumor-immune system. Presented here is the construction of a mathematical model detailing the development of progenitor and terminally exhausted CD8+ T cell populations in response to a growing tumor. Parameterization and simulation of this model captures biological dynamics observed in experimental and clinical settings. Analysis and conclusions of this model suggest population size and maintenance of progenitor exhausted CD8+ T cells should be a pillar of immunotherapy efforts. Stemming from these conclusions, it was theorized that targeting exhausted CD4+ helper T cells, which, under normal non-chronic conditions, contribute heavily to CD8+ T cell responses, would be a new and effective approach for immunotherapy. To test this hypothesis, the previously constructed model of CD8+ T cell exhaustion was expanded to incorporate CD4+ helper 1 T cells as well as immunosuppressive regulatory T cells. Simulation and analysis of this expanded model further emphasize the need to maintain progenitor exhausted CD8+ T cell numbers. Additionally, model analysis also indicated that the functionality of CD4+ T cells, both regulatory and exhausted CD4+ helper 1 T cells, played a crucial role in tumor persistence. From this work, research regarding CD4+ T cell exhaustion is strongly encouraged. With a better understanding of this dysfunction, CD4+ T cells may be a potentially effective target for future immunotherapy strategies.