Clonal Hematopoiesis Enhances Immunotherapy Response in Solid Tumors

Clonal hematopoiesis (CH), the expansion of blood cells derived from a single hematopoietic clone, is an age-related phenomenon present in over 10% of healthy adults. Around 20% of patients with solid tumors exhibit CH, meaning that a fraction of their intratumoral immune cells consequently carry CH-associated mutations. Despite this prevalence, the impact of CH on tumor biology and immunotherapy response remains poorly understood. TET2, the second most frequently mutated gene in CH, is known to modulate myeloid cell function. Herbrich and colleagues investigated how TET2-mutant CH shapes tumor immunology. In Tet2+/mut bone marrow chimeras and pancreatic cancer models, Tet2-mutant bone marrow–derived immune cells infiltrated tumors and enhanced response to immunotherapy. Comprehensive profiling revealed an increase in MHC-II+ macrophages, as well as CD4+ and CD8+ T cells in Tet2+/mut tumors. Importantly, expression profiling showed transcriptional upregulation of components for antigen presentation through both MHC-I and MHC-II. Macrophage stimulation with IFNγ had differential effects dependent on the Tet2 status, skewing Tet2+/mut macrophages towards an inflammatory, antigen-presenting phenotype. Neutralization of the IFNγ pathway in macrophages ablated the enhanced response to immunotherapy in Tet2+/mut CH mice, underscoring the pathway’s central role. Functionally, Tet2+/mut CH macrophages increased the abundance of primed, granzyme B expressing CD8+ T cells within tumors. Analysis of large clinical cohorts of patients with non–small cell lung cancer and colorectal cancer confirmed the experimental findings: Patients with TET2-mutant CH exhibited improved response to immunotherapy but no survival benefit in the absence of treatment, highlighting a specific role for TET2-mutant CH in immunotherapy. While previous studies on TET2 and myeloid cells, as well as the T-cell compartment, have produced mixed results, this work for the first time analyzes patient cohorts of sufficient size to probe an association of TET2 status and immunotherapy response. These findings position TET2 as a potential biomarker for predicting immunotherapy response in patients with cancer and concurrent CH.Herbrich S, Chaib M, Anandhan S, Andrewes SW, Nagarajan A, Guan B et al. TET2-mutant clonal hematopoiesis enhances macrophage antigen presentation and improves immune checkpoint therapy in solid tumors. Cancer Cell 2025 Oct 16 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.