Abstract C045: ATRA promotes neutrophil aging and anti-tumor immune responses in murine models of non-small cell lung cancer

Abstract Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide. While therapeutic options have improved with the introduction of immune checkpoint inhibitors (ICI) to the clinic, many patients do not respond to immunotherapy or develop resistance following initial response. A significant subset of non-small cell lung cancers (NSCLC) harbor somatic co-mutations in Kirsten rat sarcoma virus (KRAS) and Liver kinase 1 [LKB1, also known as serine/threonine kinase 11 (STK11)] genes, and are characterized by a predominance of neutrophils and an immunosuppressive tumor microenvironment (TME) often resulting in resistance to ICI. Utilizing a murine model of NSCLC, KPL-3M, with the Kras G12D P53 -/- Lkb1 -/- (KPL) genotype and an increased tumor mutational burden that recapitulates human disease, our studies revealed that all-trans retinoic acid (ATRA), a metabolite derived from vitamin A, sensitized KPL-3M tumors to PD-1 blockade. The ATRA and anti-PD-1 combination therapy improved local and systemic T cell activation and generated systemic tumor-specific immunity. To investigate ATRA-mediated anti-tumor effects, we conducted single cell RNA sequencing (scRNA-seq) of KPL-3M murine tumors with or without ATRA treatment. scRNA-seq analysis revealed a reduction of neutrophils as well as an enrichment in T and natural killer (NK) cells in the TME. scRNA-seq trajectory and RNA velocity analysis suggested an enrichment in neutrophil clusters associated with aging and effector function. ATRA increased expression of maturity markers on neutrophils isolated from KPL-3M tumors as well as differentiated in vitro from murine bone marrow and human peripheral blood progenitor cells. Preliminary data suggests a reduced neutrophil lifespan and increased turnover rate in KPL-3M tumors. Taken together, our findings reveal that ATRA reshapes the TME by altering neutrophil composition to sensitize resistant tumors to ICI immunotherapy. Citation Format: William P. Crosson, Samantha Chin, Bitta P. Kahangi, Rui Li, Raymond J. Lim, Jensen Abascal, Austin Rennels, Edgar Perez Reyes, Michael Oh, Nalani Coleman, Camelia Dumitras, Linh M. Tran, Ramin Salehi-Rad, Bin Liu, Steven Dubinett. ATRA promotes neutrophil aging and anti-tumor immune responses in murine models of non-small cell lung cancer [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C045.