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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, XiaoHua Chen, Meng Gao, Francois X. Claret, Zhiyong Ding, Jian Chen, Pingsheng Chen, Michelle C. Barton, Guang Peng, Gordon B. Mills and Amy B. Heimberger
Jiyong Liang
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: aheimber@mdanderson.org jyliang@mdanderson.org millsg@ohsu.edu
Lulu Wang
2Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Chao Wang
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3Department of Obstetrics & Gynecology, Obstetrics & Gynecology Hospital of Fu Dan University, Shanghai, China.
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Jianfeng Shen
2Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Bojin Su
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Anantha L. Marisetty
4Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Dexing Fang
4Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Cynthia Kassab
4Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Kang Jin Jeong
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Wei Zhao
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Yiling Lu
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Abhinav K. Jain
5Genes and Development Graduate Program, Department of Epigenetics and Molecular Carcinogenesis, and Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Zhicheng Zhou
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Han Liang
6Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Shao-Cong Sun
7Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Changming Lu
8The Institute of Oral Health, School of Dentistry, University of Alabama at Birmingham, Birmingham, Alabama.
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Zhi-Xiang Xu
9Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
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Qinghua Yu
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Shan Shao
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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XiaoHua Chen
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Meng Gao
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Francois X. Claret
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Zhiyong Ding
1Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jian Chen
10Department of General Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, China.
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Pingsheng Chen
11Department of Pathology, Medical School of Southeast University, Nanjing, Jiangsu, China.
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Michelle C. Barton
5Genes and Development Graduate Program, Department of Epigenetics and Molecular Carcinogenesis, and Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Guang Peng
2Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Gordon B. Mills
12Cell, Developmental & Cancer Biology, Oregon Health and Sciences University, Portland, Oregon.
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  • For correspondence: aheimber@mdanderson.org jyliang@mdanderson.org millsg@ohsu.edu
Amy B. Heimberger
4Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: aheimber@mdanderson.org jyliang@mdanderson.org millsg@ohsu.edu
DOI: 10.1158/2326-6066.CIR-19-0159 Published July 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:952–65

  • Received March 6, 2019.
  • Revision received October 7, 2019.
  • Accepted April 2, 2020.
  • Published first April 7, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (7)
July 2020
Volume 8, Issue 7
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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, XiaoHua Chen, Meng Gao, Francois X. Claret, Zhiyong Ding, Jian Chen, Pingsheng Chen, Michelle C. Barton, Guang Peng, Gordon B. Mills and Amy B. Heimberger
Cancer Immunol Res July 1 2020 (8) (7) 952-965; DOI: 10.1158/2326-6066.CIR-19-0159

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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, XiaoHua Chen, Meng Gao, Francois X. Claret, Zhiyong Ding, Jian Chen, Pingsheng Chen, Michelle C. Barton, Guang Peng, Gordon B. Mills and Amy B. Heimberger
Cancer Immunol Res July 1 2020 (8) (7) 952-965; DOI: 10.1158/2326-6066.CIR-19-0159
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