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

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)