Verteporfin inhibits PD-L1 through autophagy and the STAT1-IRF1-TRIM28 signaling axis exerting in vivo anticancer therapeutic efficacy
| Autor: | Liang, Jiyong, Wang, Lulu, Wang, Chao, Shen, Jianfeng, Su, Bojin, Marisetty, Anantha L., Fang, Dexing, Kassab, Cynthia, Jeong, Kang Jin, Zhao, Wei, Lu, Yiling, Jain, Abhinav K., Zhou, Zhicheng, Liang, Han, Sun, Shao-Cong, Lu, Changming, Xu, Zhi-Xiang, Yu, Qinghua, Shao, Shan, Chen, XiaoHua, Gao, Meng, Claret, Francois X., Ding, Zhiyong, Chen, Jian, Chen, Pingsheng, Barton, Michelle C., Peng, Guang, Mills, Gordon B., Heimberger, Amy B. |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Photosensitizing Agents
T-Lymphocytes Mice Nude Verteporfin Tripartite Motif-Containing Protein 28 Article B7-H1 Antigen Mice Inbred C57BL Disease Models Animal Mice STAT1 Transcription Factor Cell Line Tumor Neoplasms Autophagy Animals Humans Female Interferon Regulatory Factor-1 Signal Transduction |
| Zdroj: | Cancer Immunol Res |
| Popis: | PD-L1 (programmed cell death 1 ligand 1) is a key driver of tumor-mediated immune suppression, and targeting with antibodies induces therapeutic responses. Given the costs and associated toxicity, 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, identifying verteporfin as a lead small molecule inhibitor. Verteporfin suppressed basal and interferon (IFN)-induced PD-L1 expression in vitro and in vivo through Golgi-related autophagy and disruption of the STAT1-IRF1-TRIM28 signaling cascade, while not affecting the proinflammatory CIITA-MHC II cascade. Within the syngeneic tumor microenvironment, verteporfin inhibited PD-L1 expression, which was associated with enhanced T-lymphocyte infiltration. Moreover, chromatin-associated enzyme poly (ADP-ribose) polymerase 1 (PARP1) inhibition with previously documented immune modulatory effects, induces PD-L1 expression in high endothelial venules (HEVs) in tumors and when combined with verteporfin further enhanced therapeutic efficacy. Thus, verteporfin targets PD-L1 effectively through transcriptional and posttranslational mechanisms and represents an alternative therapeutic strategy for targeting PD-L1. |
| Databáze: | OpenAIRE |
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