Abstract 924: Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche

Abstract The abundant accumulation of neutrophils in various solid cancers has been well recognized, but the functions of tumor-associated neutrophils (TANs) remain controversial. TANs have long been believed to be immune suppressive and have thus been referred to as “myeloid-derived suppressor cells”. However, effective tumor control induced by immunotherapy was recently found to be associated with strong neutrophil signatures. These seemingly contradictory findings highlight the unexpected degree of plasticity and heterogeneity unique to TANs. How the cellular plasticity and functional heterogeneity of TANs are regulated remains unknown. Here, we show that, while anti-PDL1/CD40 agonist immunotherapy can induce interferon responses to reprogram many TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas, a subset of TANs residing at the tumor-stroma interface can preserve their immune suppressive state. Importantly, we identified a group of Sox2Hi tumor-initiating stem cells (tSCs) at the tumor-stroma interface that could upregulate Fatty Acid Desaturase 1 (Fads1) to produce arachidonic acid. This tSC-specific pathway enhances the autocrine prostaglandin E2 (PGE2) signaling in TANs, which can disrupt their interferon responsive potentials, preventing the interferon-mediated reprogramming. Thus, by fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity, and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse. Citation Format: Weijie Guo, Jingyun Luan, Yuxuan Miao. Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 924.