DUSP2 is a master epigenetic regulator that controls memory versus exhaustion trajectories at the branch point of effector CD8 T cells 3743

Abstract Description CD8 T cell programming creates a pool of naïve, effector, memory, or exhausted subsets, however the regulation of these trajectories is not expansively elucidated and has serious implications for cancer immunity and immune checkpoint inhibitor (ICI) therapy. We found a significant decrease of Dual Specificity Phosphatase 2 (DUSP2) in CX3CR1+ CD8s, a highly resilient subset, from ICI responders. Thus, we hypothesized that DUSP2 negatively regulates CD8 T cells in responses to ICI therapy. DUSP2 knockdown (KD) statistically improved CD8 cytotoxicity and expression of NKG7, a vital effector molecule. DUSP2 KD also increased SMARCA4 expression, a BRG/BRM-associated factor (BAF) complex ATPase, and increased open chromatin regions of BAF components. BAF complexes are chromatin remodelers implicated in CD8 differentiation pathways. In line with this, we found CD8s from DUSP2 conditional knockout (cKO) mice demonstrated a trend in defective memory generation. DUSP2 cKO CD8s also trended towards decreased PD-1 and increased CX3CR1 expression, demonstrating a more effector like phenotype. DUSP2 cKO mice did not show a significant difference in tumor protection in-vivo, presumably due to skewing of CD8 fates via BAF. Promisingly, DUSP2 KD increased ex-vivo cytotoxic functionality in about 50 percent of tested cancer patient PBMCs. Adjuvant BAF inhibition with DUSP2 KO versus KD in a specific CD8 subset may enhance responses further, providing a novel avenue for improving ICI efficacy. Funding Sources Supported by NCI 1F31CA287495-01 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)