TY - JOUR
T1 - Verteporfin inhibits PD-L1 through autophagy and the STAT1-IRF1-TRIM28 signaling axis, exerting antitumor efficacy
AU - Liang, Jiyong
AU - Wang, Lulu
AU - Wang, Chao
AU - Shen, Jianfeng
AU - Su, Bojin
AU - Marisetty, Anantha Lakshmi
AU - Fang, Dexing
AU - Kassab, Cynthia
AU - Jeong, Kang Jin
AU - Zhao, Wei
AU - Lu, Yiling
AU - Jain, Abhinav K.
AU - Zhou, Zhicheng
AU - Liang, Han
AU - Sun, Shao Cong
AU - Lu, Changming
AU - Xu, Zhi Xiang
AU - Yu, Qinghua
AU - Shao, Shan
AU - Chen, Xiao Hua
AU - Gao, Meng
AU - Claret, Francois-Xavier
AU - Ding, Zhiyong
AU - Chen, Jian
AU - Chen, Pingsheng
AU - Barton, Michelle C.
AU - Peng, Guang
AU - Mills, Gordon B
AU - Heimberger, Amy B.
N1 - Funding Information:
The authors thank Kenneth Dunner Jr at the High Resolution Electron Microscopy Facility for assistance in performing electron microscopy; David M. Wildrick, PhD, for editorial assistance; and Audria Patrick for assisting in manuscript preparation. This project was supported by the Gynecologic SPORE (5P50CA098258, NIH/NCI; to G.B. Mills), the Provost Retention Fund and the Brockman Foundation (to A.B. Heimberger), and the Shanghai Pujiang Program (17PJ1401400; to C. Wang). This research was performed in the Flow Cytometry & Cellular Imaging Facility, which is supported in part by the NIH through MD Anderson's Cancer Center Support Grant CA016672.
Funding Information:
The authors thank Kenneth Dunner Jr at the High Resolution Electron Microscopy Facility for assistance in performing electron microscopy; David M. Wildrick, PhD, for editorial assistance; and Audria Patrick for assisting in manuscript preparation. This project was supported by the Gynecologic SPORE (5P50CA098258, NIH/NCI; to G.B. Mills), the Provost Retention Fund and the
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
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.
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U2 - 10.1158/2326-6066.CIR-19-0159
DO - 10.1158/2326-6066.CIR-19-0159
M3 - Article
C2 - 32265228
AN - SCOPUS:85087469654
SN - 2326-6066
VL - 8
SP - 952
EP - 965
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 7
ER -