Abstract 1210: Modeling clonal hematopoiesis of indeterminate potential (CHIP) in solid tumors: genotype-specific effects on tumor growth and immune microenvironment

Abstract Clonal Hematopoiesis of Indeterminate Potential (CHIP) is characterized by expanded blood cell clones containing somatic mutations in leukemia-associated genes in patients without hematologic malignancies. CHIP incidence increases with age, and it is primarily associated with an increased risk of transformation to myeloid neoplasms and cardiovascular disease. Growing evidence indicates that CHIP is associated with aberrant inflammatory signaling, and retrospective analyses have revealed increased risk or poor outcomes in a wide range of diseases. We hypothesized that CHIP alters the immune response to solid tumors by dysregulating tumor-infiltrating leukocytes, resulting in increased tumor growth. Indeed, CHIP mutations have been identified in tumor-infiltrating leukocytes in patients, and some observational studies have reported an association between CHIP and decreased overall survival among patients with solid tumors. Using multiple solid tumor models, we investigated the impact of CHIP on tumor progression and the functional effects of CHIP mutations on tumor-infiltrating leukocytes. We used bone marrow transplantation to develop chimeric mouse models of CHIP containing mixtures of wild type and CHIP-mutant hematopoietic cells representing the two most common CHIP genotypes observed in patients (Dnmt3a and Tet2). Once transplants were engrafted, CHIP mice were injected with syngeneic melanoma or triple negative breast cancer cells at their orthotopic site. We observed genotype-specific effects on tumor growth, with Tet2-CHIP displaying increased tumor growth and aberrant inflammatory signaling compared to control mice. Immunophenotyping of tumor-infiltrating leukocytes uncovered altered immune infiltrate between control, Dnmt3a-CHIP, and Tet2-CHIP. We further observed a trend towards greater metastatic outgrowth in mice with CHIP, which was similarly observed in a retrospective clinical cohort of patients with breast cancer. These results suggest that while CHIP may mediate differential outcomes in solid tumors via altered immune cell function, the effects of common CHIP genotypes must each be considered independently. They further support the need for additional mechanistic and translational studies into the relationship between CHIP and solid tumors. Citation Format: Sarah C. Reed, Chad Potts, P. Brent Ferrell, Ben H. Park. Modeling clonal hematopoiesis of indeterminate potential (CHIP) in solid tumors: genotype-specific effects on tumor growth and immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1210.