PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression.
Purpose:To explore whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis, and determine whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor suppression.Experimental Design:Breast cancer cell lines, xenograft tumors, and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, IHC, and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in a syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CyTOF and FACS to evaluate the activity of antitumor immunity in the tumor microenvironment.Results:PARPi upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3β, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 resensitized PARPi-treated cancer cells to T-cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacyin vivoConclusions:Our study demonstrates a cross-talk between PARPi and tumor-associated immunosuppression and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer.Clin Cancer Res; 23(14); 3711-20. ©2017 AACR.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
Shiping
S
Jiao
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Weiya
W
Xia
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hirohito
H
Yamaguchi
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Yongkun
Y
Wei
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
Mei-Kuang
MK
Chen
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jung-Mao
JM
Hsu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical Univesity, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
Jennifer L
JL
Hsu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
Wen-Hsuan
WH
Yu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Yi
Y
Du
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Heng-Huan
HH
Lee
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Chia-Wei
CW
Li
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Chao-Kai
CK
Chou
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Seung-Oe
SO
Lim
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Shih-Shin
SS
Chang
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jennifer
J
Litton
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Banu
B
Arun
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Gabriel N
GN
Hortobagyi
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. mhung@mdanderson.org.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.|Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical Univesity, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
Mien-Chie
MC
Hung
D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D061026:Programmed Cell Death 1 Receptor; D000071137:Poly (ADP-Ribose) Polymerase-1