Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy 2034

Abstract Description Epigenetic reinforcement of T cell exhaustion is a major barrier limiting T cell responses during immunotherapy, however the core epigenetic regulators restricting anti-tumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine if they impact T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for over one year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation via H2AK119-ubiquitination and epigenetic modification of the PR-DUB pathway. Asxl1-deficient T cells synergized with anti-PDL1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients. Funding Sources Center for Translational Immunology and Immunotherapy (CeTI2) at St. Jude. NIH (R01AI114442 and R01CA237311 to BY, K08CA279926 to C.C.Z, R35CA209859 to P.J.), the NCC Network Young Investigator Award (to C.C.Z), Alex Lemonade Stand Young Investigator Grant (to C.C.Z), Van Andel- Stand up to Cancer team to B.Y., P.J., S.B., C.O., & K.G.), ASSISI Foundation funding (to B.Y.) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)