INKT CELLS CONTRIBUTE TO COLORECTAL CANCER PROGRESSION INDUCING NEUTROPHILS PRO-TUMORIGENIC FUNCTIONS

Colorectal cancer (CRC) is a multifactorial disease driven by genetic alterations, environmental factors and inflammation. Inflammation is a hallmark of cancer with opposite roles in CRC. Hyperactivation of immune cells can lead to chronic colitis and colitis-associated CRC, equally hyporesponsive immunity can promote disease progression, while anti-tumorigenic immunity efficiently limits tumor growth. Mucosal immunity is involved in the patrolling of intestinal tissues and in the maintenance of homeostasis. Disruption of intestinal homeostasis leads to different pathologies, among which CRC. Invariant Natural Killer T (iNKT) cells are a lipid-specific, CD1d-restricted population of unconventional T cells residing also in the intestinal mucosa. Although their role in inflammation, infection and in tumor immune surveillance has been extensively elucidated, iNKT cells involvement in CRC progression remains controversial. Here, by analyzing a cohort of 118 CRC patients we showed that human tumor-infiltrating iNKT cells acquire a pro-tumorigenic, exhausted phenotype characterized by high expression of PD-1, GM-CSF and IL17, while they maintain cytotoxic properties in the paired non-tumor tissue site. The phenotype of intra-tumor iNKT cells was induced by CRC-associated microbiota and Fusobacterium nucleatum (Fn). Priming with Fn did not influence the killing capabilities of iNKT cells in vitro, while it induced their expression of GM-CSF, IL17 and neutrophil-chemotactic genes. The existence of an iNKT-neutrophil crosstalk was confirmed by ex vivo correlative analysis and in vitro functional assays. Three different murine models of CRC revealed that iNKT cells promote tumor growth inducing a pro-tumorigenic polymorphonuclear-myeloid derived suppressor cell (PMN-MDSC) gene signature in tumor associated neutrophils (TANs). Importantly, in vivo treatment with αGalCer restored tumor control and iNKT cell cytotoxic functions. Survival analyses of human CRC patients showed that co-infiltration by iNKT cells and TANs led to unfavorable prognosis. Our results identified a functional role for iNKT cells in the pathogenesis of CRC, promoting pro-tumorigenic properties on TANs, and suggest a direct implication of the CRC-associated microbiota in the process. The targeted manipulation of iNKT cells restored their anti-tumorigenic properties, thus highlighting their potential use for novel cancer immunotherapies.