Abstract LB074: Targeting chromatin remodeling disrupts immune suppression by pathologically activated neutrophils in cancer

Abstract Chromatin remodelers play a critical role in regulating gene expression and chromatin organization, influencing tumor-intrinsic mechanisms linked to various immunological responses. Recent clinical evidence suggests that mutations in chromatin remodelers may enhance tumor sensitivity to immunotherapies, although the underlying mechanisms remain poorly understood. This study investigates the effects of chromatin remodeler antagonists in isogenic syngeneic tumor models with varying immunogenicity levels. Our findings demonstrate that these antagonists effectively modulate the immunosuppressive tumor microenvironment by reducing granulocytic myeloid-derived suppressor cells (G-MDSCs), also known as pathologically activated neutrophils, and enhancing the infiltration of functional CD8+ T cells. As a result, the antagonists significantly suppress tumor growth, exhibiting superior efficacy compared to anti-PD-1 monotherapy. Furthermore, they demonstrate synergistic antitumor effects when combined with anti-PD-1 treatment. This study identifies G-MDSCs as key mediators of chromatin remodeling activity and highlights the potential of specific chromatin remodeling antagonists as promising agents to improve immunotherapy responses in cancer patients. These findings contribute to our understanding of the complex interplay between chromatin remodeling, immune suppression, and cancer progression, paving the way for novel therapeutic strategies in cancer immunotherapy. Citation Format: Fan Yang, Yi Bao, Lanbo Xiao, Yuanyuan Qiao, Yizhi Cao, Arul M. Chinnaiyan. Targeting chromatin remodeling disrupts immune suppression by pathologically activated neutrophils in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB074.