Melanoma Cells Inhibit iNKT Cell Functions via PGE2 and IDO1

Invariant natural killer T (iNKT) cells are a distinct group of immune cells known for their immunoregulatory and cytotoxic activities, which are crucial in immune surveillance against tumors. They have been extensively investigated as a potential target for adoptive cell immunotherapy. Despite the initial promise of iNKT cell-based immunotherapy as a treatment for melanoma patients, its effective utilization has unfortunately yielded inconsistent outcomes. The primary cause of this failure is the immunosuppressive tumor microenvironment (TME). In this study, we specifically directed our attention towards melanoma cells, as their roles within the TME remain partially understood and require further elucidation. Methods: We conducted co-culture experiments involving melanoma cell lines and iNKT cells. Results: We demonstrated that melanoma cell lines had a significant impact on the proliferation and functions of iNKT cells. Our findings revealed that co-culture with melanoma cell lines led to a significant impairment in the expression of the NKG2D receptor and cytolytic granules in iNKT cells. Moreover, we observed a strong impairment of their cytotoxic capability induced by the presence of melanoma cells. Furthermore, through the use of selective inhibitors targeting IDO1 and COX-2, we successfully demonstrated that the melanoma cell line’s ability to impair iNKT cell activation and functions was attributed to the up-regulation of IDO1 expression and PGE2 production.