Verteporfin inhibits PD-L1 through autophagy and the STAT1-IRF1-TRIM28 signaling axis, exerting antitumor efficacy

Jiyong Liang, Lulu Wang, Chao Wang, Jianfeng Shen, Bojin Su, Anantha L. Marisetty, Dexing Fang, Cynthia Kassab, Kang Jin Jeong, Wei Zhao, Yiling Lu, Abhinav K. Jain, Zhicheng Zhou, Han Liang, Shao Cong Sun, Changming Lu, Zhi Xiang Xu, Qinghua Yu, Shan Shao, Xiao Hua ChenMeng Gao, Francois X. Claret, Zhiyong Ding, Jian Chen, Pingsheng Chen, Michelle C. Barton, Guang Peng, Gordon B. Mills, Amy B. Heimberger

    Research output: Contribution to journalArticlepeer-review

    7 Scopus citations

    Abstract

    Programmed cell death 1 ligand 1 (PD-L1) is a key driver of tumor-mediated immune suppression, and targeting it with antibodies can induce therapeutic responses. Given the costs and associated toxicity of PD-L1 blockade, alternative therapeutic strategies are needed. Using reverse-phase protein arrays to assess drugs in use or likely to enter trials, we performed a candidate drug screen for inhibitors of PD-L1 expression and identified verteporfin as a possible small-molecule inhibitor. Verteporfin suppressed basal and IFN-induced PD-L1 expression in vitro and in vivo through Golgi-related autophagy and disruption of the STAT1-IRF1-TRIM28 signaling cascade, but did not affect the proinflammatory CIITA-MHC II cascade. Within the tumor microenvironment, verteporfin inhibited PD-L1 expression, which associated with enhanced T-lymphocyte infiltration. Inhibition of chromatin-associated enzyme PARP1 induced PD-L1 expression in high endothelial venules (HEV) in tumors and, when combined with verteporfin, enhanced therapeutic efficacy. Thus, verteporfin effectively targets PD-L1 through transcriptional and posttranslational mechanisms, representing an alternative therapeutic strategy for targeting PD-L1.

    Original languageEnglish (US)
    Pages (from-to)952-965
    Number of pages14
    JournalCancer Immunology Research
    Volume8
    Issue number7
    DOIs
    StatePublished - Jul 1 2020

    ASJC Scopus subject areas

    • Immunology
    • Cancer Research

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