Elucidating the Regulation and Requirement of the NAD salvage pathway in CD8+ T Cell Exhaustion

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Project Summary The development of checkpoint based cancer immunotherapy has revolutionized cancer treatment in the last decade. Although many otherwise untreatable patients have seen long term benefit from these therapies, the long-term benefit for most patients is minimal, highlighting a need for improved treatments. A major goal of checkpoint based therapies is to reinvigorate chronically stimulated, “exhausted” CD8+ T cells to kill the tumor. Likewise, a thorough understanding of these chronically stimulated cells and their reinvigoration as compared to acutely stimulated effector CD8+ T cells will continue to be necessary for future therapeutic discovery. It has increasingly become appreciated that in addition to epigenetic and transcriptional changes, cell metabolism plays a critical role in facilitating and determining T cell fate. However, the specific metabolic requirements for exhausted CD8+ T cells before and after checkpoint based treatment remain unclear. My preliminary studies suggest that the NAD salvage pathway is a novel mediator of T cell activation and differentiation, which could be leveraged therapeutically in the context of checkpoint blockade. My data shows that 1) the NAD salvage pathway is regulated in CD8+ T cells through stimulation of both the TCR and CD28, whose signaling is known to drive cell fate determination; 2) The NAD salvage pathway is differentially required throughout the activation of naive CD8+ T cells. During the T cell exit from quiescence, activity of the rate limiting enzyme, NAMPT, is required for cell survival, proliferation, and function, but not after. I thus hypothesize that that the NAD salvage pathway is differentially regulated and required in the context of chronic versus acute antigen stimulation. In this proposal I seek to address this hypothesis by elucidating the specific signaling mechanisms that induce this pathway in CD8+ T cells (Aim 1) and determining how this pathway is regulated and required in the context of exhaustion (Aim 2). Completion of these aims will elucidate how different CD8+ T cell subsets regulate and require the NAD salvage pathway and will mechanistically inform the design of future immunotherapies designed to reinvigorate exhausted T cells.