<i>Porphyromonas gingivalis</i> fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion

Abstract

The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). The pathobiont <i>Fusobacterium nucleatum</i> influences the anti-tumor functions of CRC-infiltrating iNKT cells. However, the impact of other bacteria associated with CRC, like <i>Porphyromonas gingivalis</i>, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated <i>P. gingivalis</i> induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumor microenvironment. Mechanistically, <i>in vivo</i> and <i>in vitro</i> experiments showed that <i>P. gingivalis</i> reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery through increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how <i>P. gingivalis</i> accelerates CRC progression by inducing the upregulation of CHI3L1 in iNKT cells, thus impairing their cytotoxic functions and promoting host tumor immune evasion.