Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Somatic mutations inactivating TET2 are 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 murine models, hematopoietic Tet2 mutation enhanced the immune checkpoint blockade (ICB) response via the combined presence of phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. This murine data was clinically relevant, since tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. 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. Overall design: 9 weeks after rescue with Tet2wt or Tet2het bone marrow cells, C57Bl6/J mice were subcutaneously implanted with 250,000 MC-38 cells in the right flank. 17 days post-tumor implantation Tet2wt or Tet2het rescued mice were matched by tumor-size and assigned to receive 300 µg of anti-PD-1 blocking antibody (5 mice per genotype) or rat IgG2a isotype control (3 mice per genotype) every 2 days for 3 doses. Mice were euthanized 48 hours after the final dose and live, CD45+ tumor-infiltrating leukocytes were isolated using Fluorescence-Activated Cell Sorting. Single cells were processed using Chromium 10X 5' Single Cell and Chromium Single Cell Mouse TCR Amplification kits.