Down Regulation of c-FLIP_L Enhance PD-1 Blockade Efficacy in B16 Melanoma

Immune checkpoint blockade of programmed cell death protein 1 (PD-1) had an impressive long-lasting effect in a portion of advanced-stage melanoma patients, however, this therapy failed to induce responses in several patients; how to increase the objective response rate is very important. Cellular FLICE-inhibitory protein (c-FLIP) could inhibit apoptosis directly at the death-inducing signaling complex of death receptors and is also considered to be the main cause of immune escape. The overexpression of c-FLIP_L occurs frequently in melanoma and its expression is associated with the prognosis. We found that the level of c-FLIP_L expression was associated with the PD-1 blockade response rate in melanoma patients. Thus, we performed this research to investigate how c-FLIP_L regulates immunotherapy in melanoma. We demonstrate that down regulation of c-FLIP_L enhances the PD-1 blockade efficacy in B16 melanoma tumor model. Down regulation of c-FLIP_L could increase the tumor apoptosis and enhance the antitumor response of T cells in the lymphocyte tumor cells co-culture system. Moreover, knockdown of c-FLIP_L could decrease the expression of PD-L1 and recruit more effector T cells in the tumor microenvironment. Our results may provide a new combined therapeutic target for further improving the efficacy of PD-1 blockade in melanoma.