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Multiple studies have demonstrated synergy between immune checkpoint blockade (ICB) and radiotherapy (RT) in preclinical murine models; however, randomized trials of RT/ICB have been inconsistent in patients with solid tumors. To better understand this discordance, we hypothesized that there are non-redundant inhibitory immune pathways that restrain the efficacy of RT beyond T-cell oriented immune checkpoints. To this end, we performed scRNA-seq and CITE-seq analysis of the EO771 syngeneic murine model of breast cancer to characterize the immune landscape following RT±ICB. We found that ICB reprograms the immune response to RT by shifting tumor-associated macrophages (TAMs) from a lipid-associated phenotype (APOE, FABP5) to an M1-like interferon-stimulated state (CXCL10, ISG15). However, ICB also promoted the late recruitment of intratumoral neutrophils, which drive resistance to RT in other contexts. To evaluate whether neutrophils may be limiting antitumor immunity to RT/ICB, we depleted intratumoral neutrophils using two separate antibodies, anti-Ly6G and anti-Gr-1. Compared to RT/ICB alone, both neutrophil depletion strategies enhanced tumor control and prolonged survival in advanced EO771 tumors (P Citation Format: Anthony T. Nguyen, Tahir B. Dar, Jolene Viramontes, Satchel Stevens, Julie K. Jang, Emily Y. Ko, Diana J. Lu, Eric M. Chung, Samuel C. Zhang, Katelyn M. Atkins, Mitchell Kamrava, Howard M. Sandler, Jlenia Guarnerio, Simon Knott, Zachary S. Zumsteg, David M. Underhill, Stephen L. Shiao. Non-redundant mechanisms of immune resistance to radiotherapy converge on innate immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6409. |
