TET2-mutant clonal hematopoiesis enhances macrophage antigen presentation and improves immune checkpoint therapy in solid tumors
Shelley M. Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W. Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared C. Gilliam, Milan Radovich, Padmanee Sharma
Abstract
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.