The Role of Clonal Hematopoiesis in Lung Cancer: Immune Dysregulation and Therapeutic Targeting

/Abstract Clonal hematopoiesis (CH) is an age-related condition affecting over 20% of individuals aged 70 and older. While CH mutations are known to increase the risk of myeloid malignancies, growing evidence suggests they also contribute to lung cancer development by promoting immune suppression. However, the mechanisms linking CH-driven immunosuppression to tumor development remain poorly understood. This study aims to define how CH mutations drive non-small cell lung cancer (NSCLC) by fostering an immunosuppressive tumor microenvironment, with a specific focus on regulatory B cells (Bregs) and their interactions with myeloid-derived suppressor cells (MDSCs) and T cells. We further hypothesize that targeting IL-1β and Breg signaling can overcome CH-mediated immune suppression and enhance PD-1 blockade efficacy. To test this hypothesis, we will employ murine models of aged Tet2-deficient hematopoiesis, including orthotopic lung tumor models and bone marrow transplantation (BMT) approaches, to investigate how CH mutations promote tumor growth and suppress anti-tumor immunity. We will further evaluate the therapeutic potential of targeting IL-1β and Bregs to disrupt CH-driven immune suppression and improve PD-1 blockade efficacy in NSCLC. Lastly, to translate our findings to the clinic, we will assess the clinical impact of CH mutations on early- stage NSCLC outcomes and profile the immune microenvironment of stage IB (tumor sections) and stage II–IIIA (PBMCs) NSCLC patients using spatial transcriptomics and CITE-seq, defining CH-associated immune alterations predictive of immunotherapy response and disease recurrence. This study identifies novel immunosuppressive populations and their immune crosstalk in CH-driven lung cancer, establishing the first mechanistic link between age-related hematopoiesis and tumor immune evasion. By integrating preclinical models, patient immune profiling, and translational immunotherapy approaches, our findings will provide a new conceptual framework for CH-driven lung cancer progression. This work has the potential to inform biomarker-driven patient stratification and guide the development of targeted combination immunotherapies for CH-associated tumors. Project Number: 1R01CA300078-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Janghee Woo | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $646,181 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CDPT-C (08)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298225