NLRC5 potentiates anti-tumor CD8⁺ T cells responses by activating interferon-β in endometrial cancer

NLR family CARD domain containing 5 (NLRC5) could promote major histocompatibility complex class I (MHC-I)-dependent CD8⁺ T cell-mediated anticancer immunity. In this study, the immunosurveillance role and underlying mechanisms of NLRC5 in endometrial cancer (EC) were characterized.

CD8⁺ T cells were separated from healthy women's peripheral blood by using magnetic beads. The effect of NLRC5 and interferon-β (IFN-β) on immunosurveillance of EC were examined through a mouse tumor model and a CD8⁺ T cell-EC cell coculture system after NLRC5 overexpression and IFN-β overexpression or depletion. The effect of NLRC5 on IFN-β expression was examined with gain- and loss-of-function experiments.

NLRC5 overexpression in the EC cell and CD8⁺ T cell coculture system inhibited EC cell proliferation and migration and promoted EC cell apoptosis and CD8⁺ T cell proliferation. In vivo, NLRC5 overexpression increased the proportion of CD8⁺ T cells and inhibited EC progression. Furthermore, IFN-β overexpression in the EC cell and CD8⁺ T cell coculture system activated CD8⁺ T cell proliferation; however, genetic depletion of IFN-β exerted the opposite effects. In addition, NLRC5 could negatively regulate IFN-β expression in EC cells. Mechanistically, NLRC5 potentiated the antitumor responses of CD8⁺ T cells to EC by activating IFN-β.

Taken together, our findings demonstrated that NLRC5 potentiates anti-tumor CD8⁺ T cells responses by activating interferon-β in EC, suggesting that genetically escalated NLRC5 and IFN-β may act as potential candidates for the clinical translation of adjuvant immunotherapies to patients with EC.