Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance
(1) Deng Y (2) Xia X (3) Zhao Y (4) Zhao Z (5) Martinez C (6) Yin W (7) Yao J (8) Hang Q (9) Wu W (10) Zhang J (11) Yu Y (12) Xia W (13) Yao F (14) Zhao D (15) Sun Y (16) Ying H (17) Hung MC (18) Ma L
(1) Deng Y (2) Xia X (3) Zhao Y (4) Zhao Z (5) Martinez C (6) Yin W (7) Yao J (8) Hang Q (9) Wu W (10) Zhang J (11) Yu Y (12) Xia W (13) Yao F (14) Zhao D (15) Sun Y (16) Ying H (17) Hung MC (18) Ma L
Despite unprecedented responses of some cancers to immune checkpoint blockade (ICB) therapies, the application of checkpoint inhibitors in pancreatic cancer has been unsuccessful. Glucocorticoids and glucocorticoid receptor (GR) signaling are long thought to suppress immunity by acting on immune cells. Here we demonstrate a previously undescribed tumor cell-intrinsic role for GR in activating PD-L1 expression and repressing the major histocompatibility complex class I (MHC-I) expression in pancreatic ductal adenocarcinoma (PDAC) cells through transcriptional regulation. In mouse models of PDAC, either tumor cell-specific depletion or pharmacologic inhibition of GR leads to PD-L1 downregulation and MHC-I upregulation in tumor cells, which in turn promotes the infiltration and activity of cytotoxic T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. In patients with PDAC, GR expression correlates with high PD-L1 expression, low MHC-I expression, and poor survival. Our results reveal GR signaling in cancer cells as a tumor-intrinsic mechanism of immunosuppression and suggest that therapeutic targeting of GR is a promising way to sensitize pancreatic cancer to immunotherapy.
Author Info:
(1) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Department of Molecular and Cellular Oncology, The Un
iversity of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (2) Department of Breast Surgery, Zhejiang Cancer Hospital, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China. (3) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (4) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (5) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (6) Department of Pathology, Zhejiang Cancer Hospital, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China. (7) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (8) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (9) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (10) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (11) Department of Breast Surgery, Zhejiang Cancer Hospital, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China. (12) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (13) Hubei Hongshan Laboratory, College of Life Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, 430070, Wuhan, Hubei, China. (14) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. (15) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (16) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. (17) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. mhung@cmu.edu.tw. Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, 404, Taiwan. mhung@cmu.edu.tw. Department of Biotechnology, Asia University, Taichung, 413, Taiwan. mhung@cmu.edu.tw. (18) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. lma4@mdanderson.org. The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. lma4@mdanderson.org.
Citation: Nat Commun 2021 Dec 6 12:7041 Epub12/06/2021
