Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression

作者全名："Wang, Xiaobo; Huang, Jing; Liu, Fenglin; Yu, Qian; Wang, Ruina; Wang, Jiaqi; Zhu, Zewen; Yu, Juan; Hou, Jun; Shim, Joong Sup; Jiang, Wei; Li, Zengxia; Zhang, Yuanyuan; Dang, Yongjun"

作者地址："[Wang, Xiaobo; Yu, Qian; Wang, Ruina; Wang, Jiaqi; Zhu, Zewen; Jiang, Wei; Li, Zengxia; Dang, Yongjun] Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai, Peoples R China; [Huang, Jing; Zhang, Yuanyuan] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Ctr Chem Biol,State Key Lab Drug Res, Shanghai, Peoples R China; [Huang, Jing; Zhang, Yuanyuan] China Univ Chinese Acad Sci, Beijing, Peoples R China; [Liu, Fenglin] Fudan Univ, Zhongshan Hosp, Dept Gen Surg, Shanghai, Peoples R China; [Yu, Juan; Hou, Jun] Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China; [Shim, Joong Sup] Univ Macau, Fac Hlth Sci, Dept Pharmaceut Sci, Taipa, Macao, Peoples R China; [Shim, Joong Sup] Univ Macau, Fac Hlth Sci, Canc Ctr, Taipa, Macao, Peoples R China; [Dang, Yongjun] Chongqing Med Univ, Affiliated Hosp 2, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing, Peoples R China; [Dang, Yongjun] Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, 1 Yixueyuan Rd Bldg Lib,8th Floor, Chongqing 400016, Peoples R China; [Zhang, Yuanyuan] Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; [Jiang, Wei; Li, Zengxia] Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, 131 Dong Rd, Shanghai 200032, Peoples R China"

通信作者："Dang, YJ (通讯作者)，Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, 1 Yixueyuan Rd Bldg Lib,8th Floor, Chongqing 400016, Peoples R China.; Zhang, YY (通讯作者)，Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.; Jiang, W; Li, ZX (通讯作者)，Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, 131 Dong Rd, Shanghai 200032, Peoples R China."

来源：JOURNAL OF CLINICAL INVESTIGATION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000996388600002

JCR分区：Q1

影响因子：13.3

年份：2023

卷号：133

期号：9

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-KB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors."

基金机构："National Natural Science Foundation of China [22137002, 21877016, 81820108030, 81772962, 92253305, 82273021, 81972621, 82273946, 81803554]; National Key Research and Development Program of China [2022YFC2804800]; Open Project of the State Key Laboratory of Respiratory Diseases [SKLRD-OP-202213]; University Innovation Research Group in Chongqing [CXQT21016]; Chongqing Talent Program Project [CQYC20200302119]; High-Level Innovation Platform Cultivation Plan of Chongqing; Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing"

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (22137002 and 21877016, to YD; 81820108030 and 81772962, to ZL; 92253305, 82273021, and 81972621, to WJ; and 82273946 and 81803554, to YZ); the National Key Research and Development Program of China (2022YFC2804800, to WJ); the Open Project of the State Key Laboratory of Respiratory Diseases (SKLRD-OP-202213, to YZ); the University Innovation Research Group in Chongqing (CXQT21016, to YD); the Chongqing Talent Program Project (CQYC20200302119, to YD); the High-Level Innovation Platform Cultivation Plan of Chongqing (to YD); and the Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing (to YD)."