The role of Tet2-mutant clonal hematopoiesis in solid tumor immunology

作者：Shelley M. Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W. Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared C. Gilliam, Milan Radovich, Padmanee Sharma · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-4952 · 研究领域：Acute Myeloid Leukemia Research、Single-cell and spatial transcriptomics、Immune cells in cancer

Abstract Background: Clonal hematopoiesis (CH) is an age-related condition wherein somatic mutations in hematopoietic stem and progenitor cells lead to overrepresentation of mature immune cells that harbor the same mutation, affecting approximately 10% of older adults. While CH is primarily associated with increased risk of myeloid malignancy and some cardiovascular disease, recent evidence suggests that it is detectable in more than 20% of patients with solid tumors. In such patients, infiltrating myeloid cells harboring the same CH mutations have been detected at appreciable levels in tumor tissue and correlate with poor patient outcomes across cancer types. The impact of CH in the solid tumor immune microenvironment and response to immune checkpoint therapy (ICT) is unknown. Methods: To mechanistically study the effects of CH on solid tumor biology in vivo, we established orthotopic models of pancreatic adenocarcinoma (PDAC) and melanoma in bone marrow chimera mice that harbor a CH clone heterozygous for a loss of function mutation in Tet2 (Tet2+/mut); the second most mutated gene seen in human CH. Briefly, lethally irradiated CD45.1 recipient mice were transplanted with either Tet2+/mut CD45.2 cells or wild-type (WT; Tet2+/+) CD45.2. Following complete bone marrow reconstitution, mice were orthotopically implanted with mT4 pancreatic tumor cells (KPC-derived PDAC model) or B16-F10 melanoma cells. CH and WT mice were randomized to receive 3 doses of either a vehicle contro...