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

Yalan Deng,Li Ma,Jie Zhang,Mien-Chie Hung,Wenjuan Yin,Yang Zhao,Di Zhao,Zilong Zhao,Consuelo Martinez,Xianghou Xia,Haoqiang Ying,Weiya Xia,Weiche Wu,Yutong Sun,Jun Yao,Yang Yu,Qinglei Hang,Fan Yao

doi:10.1038/s41467-021-27349-7

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.

Highlights

Despite unprecedented responses of some cancers to immune checkpoint blockade (ICB) therapies, the application of checkpoint inhibitors in pancreatic cancer has been unsuccessful
We show that glucocorticoid receptor (GR) acts as a transcriptional activator of PD-L1 and a transcriptional repressor of the major histocompatibility complex class I (MHC-I) in pancreatic cancer cells, and that GR depletion or inhibition promotes the infiltration and activity of cytotoxic T cells, leading to enhanced immune surveillance and sensitization of pancreatic tumors to immune checkpoint inhibitors
To determine whether GR regulates immunity-related genes in pancreatic cancer cells, we treated two human pancreatic ductal adenocarcinoma (PDAC) cell lines harboring the G12D hotspot mutation of KRAS24,25, SU86.86 and SW1990, with the clinical GR antagonist mifepristone26–28. qPCR analysis revealed that mifepristone treatment of both cell lines decreased mRNA levels of several immune checkpoint ligands[29], including PD-L1, CD47, TDO, and SIGLEC15 (Fig. 1a and Supplementary Fig. 1a), and increased mRNA levels of several components in the MHC-I pathway, including HLA-A, HLA-B, HLA-C, B2M, SEC61B, and SEC61G (Fig. 1b and Supplementary Fig. 1b)

Summary

Introduction

Despite unprecedented responses of some cancers to immune checkpoint blockade (ICB) therapies, the application of checkpoint inhibitors in pancreatic cancer has been unsuccessful. GR can induce metastatic ability of breast cancer cells by upregulating the kinase ROR121 and promote anti-androgen resistance of prostate cancer cells by substituting for the androgen receptor to activate target genes[22,23] It is unknown whether GR signaling in cancer cells exerts an immunosuppressive effect on the TME, and if so, whether this can be exploited to sensitize “cold” tumors such as pancreatic cancer to ICB therapy. We show that GR acts as a transcriptional activator of PD-L1 and a transcriptional repressor of the major histocompatibility complex class I (MHC-I) in pancreatic cancer cells, and that GR depletion or inhibition promotes the infiltration and activity of cytotoxic T cells, leading to enhanced immune surveillance and sensitization of pancreatic tumors to immune checkpoint inhibitors

Methods

Results

Conclusion