Abstract 6820: Age-related clonal hematopoiesis drives immune remodeling that promotes lung cancer and alters neoadjuvant chemo-immunotherapy outcomes

Abstract More than 20% of individuals ≥70 harbor clonal hematopoiesis (CH) mutations without overt malignancy. CH has been linked to elevated risk of non-hematologic cancers, particularly lung cancer, although causality remains unresolved. The TRACERx study showed that CH in blood and tumor predicts higher recurrence and mortality in NSCLC, and recent reports suggest that TET2-mutant CH may enhance immunotherapy responsiveness. However, how CH shapes lung tumorigenesis and modulates neoadjuvant immunotherapy outcomes in early-stage lung cancer remains unclear. We performed integrated analyses in murine models and NSCLC patients, identifying a CH-driven immunosuppressive program. To test whether age-associated Tet2-mutant hematopoiesis accelerates lung cancer, KP (KrasG12D;Trp53-/-) lung cancer cells were orthotopically implanted into young (8-week) and aged (30-week) Tet2-null (Tet2fl/fl;VavCre), Tet2-heterozygous (Tet2fl/+;VavCre), and WT mice. Aged Tet2-deficient mice developed tumors earlier and with greater burden compared to young counterparts. Spleen and tumor profiling showed expansion of CD11b+ myeloid cells, Tregs, and PD-1+ T cells, with profound NK-cell depletion in older Tet2-deficient mice, indicating enhanced immune suppression in aged Tet2-deficient hosts. We next profiled PBMCs from 59 NSCLC patients using scRNA-seq. Individuals with TET2-mutant CH (n=5) exhibited enrichment of MDSCs, Tregs, effector and exhausted T cells, along with significant reductions in naïve T cells and activated NK cells compared with CH-negative patients (n=45). Long-read variant calling from scRNA-seq further revealed that within CH-positive individuals, both wild-type and CH-mutant immune cells adopted similarly aberrant immune states, unlike those from CH-negative individuals. Ligand-receptor modeling indicated that myeloid cells predominantly drove CD4 T-cell alterations, whereas CD8 T-cell remodeling arose from B- and T-cell interactions—highlighting global immune rewiring triggered by limited CH-derived clones through repeated immune synaptic interactions. Finally, in the real-NADIM cohort treated with neoadjuvant immunotherapy (n=161), patients with CH mutations showed comparable response rates but improved cancer-specific and overall survival compared with CH-negative patients, with this preliminary evidence supporting the idea that CH-induced immune alterations can be therapeutically reprogrammed. Conclusion: age-associated TET2-mutant CH remodels systemic immunity to create tumor-promoting microenvironments. These effects appear reversible with immunotherapy. Ongoing work is evaluating combination strategies targeting both myeloid and T-cell pathways to intercept CH-mediated immune escape in age-associated Tet2-deficient CH and includes spatial transcriptomic analysis of early-stage NSCLCs. Citation Format: Kernyu Park, Eunyoung Kim, Maria Belen Sierra-Rodero, Yohan Byun, Tarrant McPherson, Shivani Kapadia, Derrick Bayer, Julia Yoo, Suresh S. Ramalingam, Woong-Yang Park, Bosch Bosch, Noemi Reguart, Bartomeu massuti_, Alberto Cruz-Vermudez, Mariano Provencio, Janghee Woo. Age-related clonal hematopoiesis drives immune remodeling that promotes lung cancer and alters neoadjuvant chemo-immunotherapy outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6820.