PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression.
PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression.
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DOI：
10.1158/1078-0432.ccr-16-3215
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发表时间：
2017-07-15
期刊：
影响因子：
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通讯作者：
Hung MC
中科院分区：
文献类型：
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作者：
Jiao S;Xia W;Yamaguchi H;Wei Y;Chen MK;Hsu JM;Hsu JL;Yu WH;Du Y;Lee HH;Li CW;Chou CK;Lim SO;Chang SS;Litton J;Arun B;Hortobagyi GN;Hung MC
探索PARP抑制与PD-L1/ PD-1免疫检查点轴之间是否存在串扰，并确定PD-L1/ PD-1阻断是否增强PARP抑制剂（PARPi）的肿瘤抑制作用。通过免疫印迹、免疫组织化学和FACS分析评估用PARPi处理的乳腺癌细胞系、异种移植肿瘤和同基因肿瘤的PD-L1表达。使用磷酸激酶抗体阵列筛选来探索PARPi诱导的PD-L1上调的潜在机制。在同基因肿瘤模型中测试单独PARPi、单独PD-L1阻断或其组合的治疗功效。通过CytoF和FACS分析从同源肿瘤分离的肿瘤浸润淋巴细胞和肿瘤细胞，以评估肿瘤微环境中的抗肿瘤免疫活性。PARP在乳腺癌细胞系和动物模型中上调PD-L1表达。从机制上讲，PARPi使GSK 3 β失活，这反过来又增强了PARPi介导的PD-L1上调。PARPi通过上调PD-L1减弱抗癌免疫，并且PD-L1的阻断使PARPi处理的癌细胞对T细胞杀伤重新敏感。PARPi和抗PD-L1疗法的组合与每种药剂单独相比显著增加了体内治疗功效。我们的研究证明了PARPi和肿瘤相关免疫抑制之间的串扰，并提供证据支持PARPi和PD-L1或PD-1免疫检查点阻断的组合作为治疗乳腺癌的潜在治疗方法。
To explore whether a crosstalk exists between PARP inhibition and PD-L1/ PD-1 immune checkpoint axis, and determine if blockade of PD-L1/ PD-1 potentiates PARP inhibitor (PARPi) in tumor suppression. Breast cancer cell lines, xenograft tumors and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, immunohistochemistry 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 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 anti-tumor immunity in the tumor microenvironment. PARPis 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 re-sensitized 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 efficacy in vivo. Our study demonstrates a crosstalk 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.