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

Award Number: R01CA300078
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/02/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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The Role of Clonal Hematopoiesis in Lung Cancer: Immune Dysregulation and Therapeutic Targeting - Project Summary/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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $646,181 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	000	1	4/6/2026	NEW	$646,181
														Subtotal = $646,181

Grand Total All Awards = $646,181

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

Award Number: R01CA300078

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/02/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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