iNKT cell-neutrophil crosstalk promotes colorectal cancer pathogenesis

: iNKT cells account for a relevant fraction of effector T-cells in the intestine and are considered an attractive platform for cancer immunotherapy. Although iNKT cells are cytotoxic lymphocytes, their functional role in colorectal cancer (CRC) is still controversial, limiting their therapeutic use. To gain insights into iNKT cells role in CRC we examined the immune cell composition and iNKT cell phenotype of CRC lesions in patients (n=118) and different murine models. High-dimensional single-cell flow cytometry, metagenomics and RNAseq experiments revealed that iNKT cells are enriched in tumor lesions. The tumor-associated pathobiont Fusobacterium nucleatum induces IL17 and GM-CSF expression in iNKT cells without affecting their cytotoxic capability but promoting iNKT-mediated recruitment of neutrophils with PMN-MDSCs-like phenotype and functions. Lack of iNKT cells reduced tumor burden and recruitment of immune suppressive neutrophils. iNKT cells in vivo activation with αGalCer restored their anti-tumor function suggesting that iNKT cells can be modulated to overcome CRC-associated immune evasion. Tumor co-infiltration by iNKT cells and neutrophils correlates with negative clinical outcomes highlighting the importance of iNKT cells in the pathophysiology of CRC. Our results reveal a functional plasticity of iNKT cells in CRC suggesting a pivotal role of iNKT cells in shaping the TME with relevant implications for treatment.