RT Journal Article
SR Electronic
T1 Verteporfin Inhibits PD-L1 through Autophagy and the STAT1–IRF1–TRIM28 Signaling Axis, Exerting Antitumor Efficacy
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 952
OP 965
DO 10.1158/2326-6066.CIR-19-0159
VO 8
IS 7
A1 Liang, Jiyong
A1 Wang, Lulu
A1 Wang, Chao
A1 Shen, Jianfeng
A1 Su, Bojin
A1 Marisetty, Anantha L.
A1 Fang, Dexing
A1 Kassab, Cynthia
A1 Jeong, Kang Jin
A1 Zhao, Wei
A1 Lu, Yiling
A1 Jain, Abhinav K.
A1 Zhou, Zhicheng
A1 Liang, Han
A1 Sun, Shao-Cong
A1 Lu, Changming
A1 Xu, Zhi-Xiang
A1 Yu, Qinghua
A1 Shao, Shan
A1 Chen, XiaoHua
A1 Gao, Meng
A1 Claret, Francois X.
A1 Ding, Zhiyong
A1 Chen, Jian
A1 Chen, Pingsheng
A1 Barton, Michelle C.
A1 Peng, Guang
A1 Mills, Gordon B.
A1 Heimberger, Amy B.
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/8/7/952.abstract
AB 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.