SA-49, a Novel Aloperine Derivative, Induces MITF-Dependent Lysosomal Degradation of PD-L1
46 Pages Posted: 4 Dec 2018More...
Programmed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Small-molecule checkpoint inhibitors blocking PD-L1 function are urgently needed. Here we reported that SA-49, a novel aloperine derivative, decreased the expression of PD-L1 in NSCLC cells and enhanced the cytotoxicity of co-cultured T and NK cells. Importantly, we found lysosomal pathway contributed to SA-49-mediated down-regulation of PD-L1. SA-49 increased the biogenesis of lysosome and promoted translocation of PD-L1 to lysosome for proteolysis, which was associated with nuclear translocation of MITF. SA-49-induced MITF translocation acted through activation of PKCα and subsequently suppression of GSK3β activity. Furthermore, SA-49 suppressed Lewis tumor xenograft growth by activating immune microenvironment in C57BL/6 mice. Our data demonstrate that SA-49 can be used to regulate PD-L1 in cancer cells and trigger its degradation by activating lysosome function.
Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81773782, 81473248 and 81621064) and CAMS Major Collaborative Innovation Project (2016-12M-1-011).
Declaration of Interests: The authors have declared no conflicts of interest.
Ethics Approval Statement: The animal procedures were carried out with the approval of the Animal Ethics Committee of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences.
Keywords: Aloperine; PD-L1; Lysosome; MITF; Checkpoint Inhibitors
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