TET2-mutant clonal hematopoiesis enhances macrophage antigen presentation and improves immune checkpoint therapy in solid tumors

Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of Tet2 +/mut CH in mice with solid tumors, we found the Tet2 -mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2 +/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8 + T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients and 25,064 colorectal adenocarcinoma patients , TET2- mutant CH is associated with improved outcome specifically with ICT. This study proposes a role for Tet2 +/mut antigen presenting macrophages in shaping antitumor immunity and identifies TET2- mutant CH as a potential biomarker for improved response to ICT in patients with solid tumors. • TET2 clonal hematopoiesis facilitates improved response to checkpoint therapy • TET2-mutant macrophages show heightened IFNγ response and polarization • TET2-mutant macrophages more effectively cross-prime CD8 + T cells Herbrich et al. demonstrate that TET2-mutant clonal hematopoiesis improves response to immune checkpoint therapy in the context of solid tumors. Intratumoral TET2-mutant macrophages are immunogenic antigen-presenting cells in the presence of IFNγ and facilitate more potent CD8 + T cell cross-priming, ultimately leading to improved response to immunotherapy.