Intra-tumoral microbiota and host genotype cooperatively shape neutrophil antitumor activity in colorectal cancer

Colorectal cancer (CRC) represents a major cause of cancer related death worldwide. Defined genetic alterations are known to underlie CRC oncogenesis. However, in the last decades a critical role of the composition of tumor microenvironment has also been recognized. While tumor infiltration by T lymphocytes has been consistently recognized to predict improved clinical outcome, the role of tumor-associated neutrophils (TANs) in CRC is still debated.CRC develops in a microbiota-rich environment, and barrier dysfunction allows bacterial translocation into the mucosa. Neutrophils, as first responders to bacteria, may interact with tumor-infiltrating bacteria. However, the functional outcome and prognostic relevance of these interactions have not been thoroughly investigated. Here we unravel that TAN recruitment and functions are modulated by intra-tumoral microbiota and only defined bacterial species are able to unleash TANs' antitumor potential. Fusobacterium nucleatum (Fn) promotes expression of neutrophil-recruiting chemokines in tumor cells and enhances neutrophil migration more efficiently than Bacteroides fragilis (Bf). Importantly, Fn, but not Bf, triggers neutrophils to release cytotoxic proteins showing tumoricidal activity in vitro and in xenograft models. Mechanistically, these antitumor effects are elicited upon Fn binding to an activatory receptor (R-a) expressed on neutrophils but are impaired upon R-a blockade or in neutrophils from donors carrying a R-a loss-of-function polymorphism. Supporting these findings, in human CRCs, elevated Fn loads, high TANs densities, and expression of wild-type, but not polymorphic, R-a allele, correlate with improved patient survival. Our findings identify microbiota composition and host genetic background as critical determinants of TAN functional profiles and offer insights into neutrophil-targeted therapeutic strategies in CRC.