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

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.