Abstract
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-FLIPL occurs frequently in melanoma and its expression is associated with the prognosis. We found that the level of c-FLIPL expression was associated with the PD-1 blockade response rate in melanoma patients. Thus, we performed this research to investigate how c-FLIPL regulates immunotherapy in melanoma. We demonstrate that down regulation of c-FLIPL enhances the PD-1 blockade efficacy in B16 melanoma tumor model. Down regulation of c-FLIPL 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-FLIPL 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.
Highlights
PD-1 and its ligand PD-L1 signaling pathway are important mechanisms that tumors use to escape antitumor immunity
The expression of CASP8 and FADD-like apoptosis regulator (c-FLIPL) was not associated with progression-free survival (PFS), the c-FLIPL expression seems to trend with the PD-1 blockade response rate (Figure 1F)
We explored that the expression of c-FLIPL was correlated with the PD-1 response rate in melanoma patients
Summary
PD-1 and its ligand PD-L1 signaling pathway are important mechanisms that tumors use to escape antitumor immunity. It is imperative to develop more aggressive treatment which could improve the efficiency and cure rate of patients. In order to help understanding the tumor immune response and designing the immunotherapy, Daniel S proposed the concept of “cancer-immunity cycle,” referring to seven key links initiated in the anticancer immune response which could lead to effective killing of cancerous cells [5]. The therapeutic effect of checkpoint blockade c-FLIPL Affects PD-1 Blockade Efficacy could be further improved by an enhanced killing effect of T cells. There are two dominant apoptosis-related signaling pathways: the Fas/Fas ligand (FasL) mediated ligand-binding external pathway and the mitochondrial dependent internal pathway [7]. More efficient immune therapy depends on the functional integrity of the extrinsic pathway
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