Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance

• Published in: Nature communications Vol. 12; no. 1; pp. 7041 - 16
• Main Authors: Deng, Yalan, Xia, Xianghou, Zhao, Yang, Zhao, Zilong, Martinez, Consuelo, Yin, Wenjuan, Yao, Jun, Hang, Qinglei, Wu, Weiche, Zhang, Jie, Yu, Yang, Xia, Weiya, Yao, Fan, Zhao, Di, Sun, Yutong, Ying, Haoqiang, Hung, Mien-Chie, Ma, Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/105; 13/31; 13/51; 38/15; 59/57; 631/67/1059/2325; 631/67/1504/1713; 64/60; 96/106; Adenocarcinoma; Animal models; Animals; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - therapy; Cell Line, Tumor; Cytotoxicity; Depletion; Drug resistance; Gene Expression Regulation, Neoplastic; Gene regulation; Glucocorticoids; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Humanities and Social Sciences; Humans; Immune checkpoint; Immune evasion; Immune system; Immunity; Immunoblotting; Immunosuppression; Immunotherapy; Immunotherapy - methods; Kaplan-Meier Estimate; Kinases; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Metastases; Mice; Mice, Inbred C57BL; multidisciplinary; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - therapy; PD-L1 protein; Receptors; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - immunology; Receptors, Glucocorticoid - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Science; Science (multidisciplinary); Signaling; Therapeutic targets; Transcription; Tumor cells; Tumor Escape - genetics; Tumor Escape - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27349-7

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. Glucocorticoids and glucocorticoid receptor (GR) signalling can suppress anti-tumour immunity. Here the authors show that GR activates PD-L1 expression and represses MHC-I expression in pancreatic cancer cells, while GR inhibition enhances anti-tumour immunity and sensitises the cancer cells to immunotherapy.