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

Yalan Deng, Xianghou Xia, Yang Zhao, Zilong Zhao, Consuelo Martinez, Wenjuan Yin, Jun Yao, Qinglei Hang, Weiche Wu, Jie Zhang, Yang Yu, Weiya Xia, Fan Yao, Di Zhao, Yutong Sun, Haoqiang Ying, Mien-Chie Hung () and Li Ma ()
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Yalan Deng: The University of Texas MD Anderson Cancer Center
Xianghou Xia: Chinese Academy of Sciences
Yang Zhao: The University of Texas MD Anderson Cancer Center
Zilong Zhao: The University of Texas MD Anderson Cancer Center
Consuelo Martinez: The University of Texas MD Anderson Cancer Center
Wenjuan Yin: Chinese Academy of Sciences
Jun Yao: The University of Texas MD Anderson Cancer Center
Qinglei Hang: The University of Texas MD Anderson Cancer Center
Weiche Wu: The University of Texas MD Anderson Cancer Center
Jie Zhang: The University of Texas MD Anderson Cancer Center
Yang Yu: Chinese Academy of Sciences
Weiya Xia: The University of Texas MD Anderson Cancer Center
Fan Yao: Huazhong Agricultural University
Di Zhao: The University of Texas MD Anderson Cancer Center
Yutong Sun: The University of Texas MD Anderson Cancer Center
Haoqiang Ying: The University of Texas MD Anderson Cancer Center
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center
Li Ma: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27349-7

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