Tumor-initiating stem cells fine-tunes the neutrophil plasticity to drive immunotherapy relapse 2392

Description 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, in squamous cell carcinomas, we show that, while anti-PDL1/CD40 agonist immunotherapy can modulate TAN plasticity and reprogram many TANs, allowing them to regain anti-tumor activities, 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 can disrupt the interferon responsive potentials of TAns, 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. Funding Sources NIH/NCI R01CA285786 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)