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

• DOI: 10.1038/s41467-021-27349-7
• Publication Date: 2021-12-06T11:06:05Z
• Authors: 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; Li Ma
• Keywords: Immune checkpoint; Cancer Immunotherapy

Abstract Despite unprecedented responses of some cancers to immune checkpoint blockade (ICB) therapies, the application inhibitors in pancreatic cancer has been unsuccessful. Glucocorticoids and glucocorticoid receptor (GR) signaling are long thought suppress immunity by acting on cells. Here we demonstrate a previously undescribed tumor cell-intrinsic role for GR activating PD-L1 expression repressing major histocompatibility complex class I (MHC-I) ductal adenocarcinoma (PDAC) cells through transcriptional regulation. In mouse models PDAC, either cell-specific depletion or pharmacologic inhibition leads downregulation MHC-I upregulation cells, which turn promotes infiltration activity cytotoxic T enhances anti-tumor immunity, overcomes resistance ICB therapy. patients with correlates high expression, low poor survival. Our results reveal as tumor-intrinsic mechanism immunosuppression suggest that therapeutic targeting is promising way sensitize immunotherapy.