Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Abstract

Somatic mutations inactivatingTET2are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoieticTet2mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response withTet2mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, inTet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression.Tet2-mutant monocytes activated costimulatory programs, whileTet2-mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients withTET2driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.