Elucidating the role of NF-kB signaling in CD8 T cell Exhaustion

About This Grant

PROJECT SUMMARY/ ABSTRACT Cancer and chronic viral infections affect millions, with cancer being a leading cause of death. Despite significant advancements in treatment, there is a critical need to identify new therapeutic targets and enhance existing therapies. Immunotherapy, particularly immune checkpoint blockade (ICB) and adoptive cell therapy (ACT), have emerged as promising strategies; however, many patients do not respond due to CD8 T cell exhaustion, which occurs when T cells are persistently exposed to antigen and progressively lose their function. The presence of terminally exhausted (TTerm) T cells often results in poor ICB responses, and cells used for ACT often become ineffective in the tumor microenvironment (TME) due to exhaustion. Thus, discovering strategies to prevent or reverse T cell exhaustion is essential for improving immunotherapy outcomes. Epigenetic programming contributes to exhaustion progression by silencing effector-related genes through DNA methylation, which reduces T cell responsiveness to ICB. However, the upstream factors regulating this epigenetic programming in CD8 T cells remain unexplored. Among these factors is T cell receptor (TCR) signaling pathways. One such pathway activates nuclear factor of activated T cells (NFAT), known to promote exhaustion by upregulating immune checkpoints. Our preliminary studies indicate that NFAT signaling can be activated upon stimulation in all exhausted T cell (TEX) populations, suggesting this pathway is not impaired in Tex cells. Another well-known TCR pathway activates the nuclear factor-B (NF-B), which is crucial for T cell development, memory maintenance, and effector function; however, the role of NF-B signaling in the context of T cell exhaustion is largely unknown. Preliminary data suggest NF-B signaling is impaired in exhausted T cells, with its nuclear translocation as well as signaling ability decreasing through the progression of exhaustion. However, it is the most active in the progenitor population, which is associated with better ICB responses. Our preliminary data also suggest that boosting NF-B signals in chronically infected mice increases the number of progenitor exhausted cells. Because of this, we hypothesize that NF-B signals epigenetically remodels TEX cells by maintaining their stemness features, thereby increasing their ICB responsiveness, while decreasing their progression towards terminal exhaustion. To test this hypothesis, we will employ a TCR reporter system in murine CD8 T cells, followed by exhaustion modeling and epigenetic assays (Aim 1). We will also evaluate the efficacy of NF-B/NFAT signal rebalancing in treating chronic infections and cancer by adjusting these signals in cells used for ACT and in murine models receiving ICB therapy (Aim 2). Overall, this project aims to improve our understanding of NF-B signaling in TEX cells and enhance immunotherapy effectiveness. The completion of this project also aligns with my outlined training plan and will further my skills in immunotherapy research and scientific communication, taking place in a positive environment and under skilled mentorship.