Identification of anti-tumoral neutrophil states from pan-cancer single-cell transcriptome analysis of immunotherapies in preclinical mouse models and humans 3571

Abstract Description Neutrophils, the most abundant immune cells, have multifaceted functions in cancers. While most previous work reported pro-tumoral neutrophils, emerging data have shown anti-tumoral phenotypes directly killing tumor cells and activating cytotoxic T-cell immunity in different immunotherapy contexts. Therefore, there is a need to define anti-tumoral neutrophil markers and potential therapeutic targets. Here, we interrogate anti-tumoral phenotypes using bioinformatics analysis of ∼95,000 neutrophils from scRNA-Seq of 8 mouse models with different treatments, including Immune Checkpoint Blockade (ICB) and CD40 agonist. In addition, we generated multi-omics single-cells of neutrophils from immunological cold models using a combined neutrophil activation therapy. We found consistent markers of interferon-stimulated neutrophil phenotypes in multiple cancer types and treatments. The compendium of pan-cancer pan-treatment data helps identify potential markers of neutrophils with tumor-killing phenotypes found in microbial stimulation and tumor gene knock-out settings. Furthermore, our new scRNA-Seq data determined a subset associated with TNF and migration phenotypes. Lastly, cross-species analysis with data across 17 cancer types, including those treated with ICB, determined similar signatures in humans. Our results report the emerging phenotypes in anti-tumoral neutrophils revealed by single-cell omics, providing a foundation for future mechanistic and translational studies. Topic Categories Computational and Systems Immunology (COMP)