PORPHYROMONAS GINGIVALIS CONTRIBUTES TO COLON CANCER PROGRESSION BY ENHANCING INKT CELL PRO-TUMORIGENIC FUNCTIONS

Colorectal cancer (CRC) is characterized by a complex tumor microenvironment. Invariant Natural Killer T (iNKT) cells are a CD1d-restricted, lipid-specific, T cell population known to be pro-tumorigenic in CRC. On the other hand, the microbiota has gained importance for its infuence over cancer cells and, most importantly, the immune system. Porphyromonas gingivalis is a member of the oral microbiota linked to CRC. Although the pro-tumor functions of iNKT cells in CRC are known, how they acquire these features is not well understood. Hence, we aimed at understanding if iNKT cells become pro-tumorigenic due to signals given by CRC-associated bacteria, in particular P. gingivalis. For this, we used two murine models and functional assays with human iNKT cell lines. We observed that CRC cells did not induce IL-17, GM-CSF and IL-10 production, known to be secreted by pro-tumorigenic iNKT cells, but activated iNKT cell cytotoxicity via the perforin/granzyme pathway. P. gingivalis enhanced the expression of pro-tumor cytokines and neutrophil chemoattractant activity on tumor-infiltrating iNKT cells in vivo. Furthermore, we found that iNKT cells are necessary for the pro-tumorigenic effects of P. gingivalis in the AOM/DSS model. In vitro experiments revealed that P. gingivalis-primed cells have a neutrophil chemotactic signature and diminished cytotoxicity. Moreover, we showed that Toll-like receptor 2 and 4 signaling mediates the increase in IL-10 and GM-CSF production, whereas chitinase 3-like protein 1 is responsible for the impaired killing activity. These results identified a novel mechanism of P. gingivalis in CRC pathogenesis, by acting on unconventional T cell activities.