Clonal hematopoiesis (CH), marked by somatic mutations in a blood cell clone, is common in aging and is associated with an increased risk of future leukemia as well as nonhematologic diseases. In solid tumors, the presence of CH is linked to faster cancer progression and poor outcomes, yet its role in tumor immunity is complex. Previous studies implicated CH, particularly driven by TET2 mutations, in creating a myeloid-rich, proinflammatory immunosuppressive tumor microenvironment (TME), whereas TET2 disruption enhanced the performance of chimeric antigen receptor T-cell therapy. In this issue of Cancer Research, Rondeau and colleagues investigated the role of TET2-CH in promoting response to immune checkpoint blockade (ICB). In a model of hematopoietic Tet2 inactivation in mice implanted with syngeneic flank tumors, the authors found increased efficacy of anti–PD-1 ICB, which required both myeloid and T cells. Mechanistically, Tet2-deficient T cells were biased toward memory states, curbing exhaustion and regulatory phenotypes, whereas myeloid cells shifted from immunosuppressive to costimulatory programs with PD-1 blockade. Consistently, in patients with colorectal cancer and melanoma, TET2-CH was associated with an immune-rich TME and greater odds of clinical benefit from ICB. These findings suggest that TET2-CH may serve as a biomarker of accentuated cancer immunotherapy response, providing novel insights into its role in the TME. See related article by Rondeau et al., p. 845
Yuan et al. (Mon,) studied this question.