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

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.

Novel immunosuppressive effect of FK506 by upregulation of PD‐L1 via FKBP51 in heart transplantation

“…GCs can enhance the expression of PD‐L1 in DCs through the GC‐induced leucine zipper 46 and prevent antigen‐specific T lymphocyte response 47 . Furthermore, the GC receptor can regulate PD‐L1 and MHC‐I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance 48 . Interestingly, according to another study on alcohol‐induced GC feedback circuit, FKBP51 was involved in glucocorticoid regulation.…”

“…47 Furthermore, the GC receptor can regulate PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance. 48 Interestingly, according to another study on alcoholinduced GC feedback circuit, FKBP51 was involved in glucocorticoid regulation. They found that FKBP51 inhibition by SAFit2 can block GC signalling pathways and reduce alcohol consumption.…”

Current insight into the regulation of PD-L1 in cancer

“…In melanoma, regorafenib inhibits JAK1/2-STAT1 and MAPK signaling by targeting the RET-Src axis, consequently attenuating IFN-γ-induced PD-L1 expression [ 146 ]. A previous study has reported that the glucocorticoid receptor inhibitor mifepristone and dual ICB act synergistically in PC to inhibit PD-L1 expression while promoting cytotoxic T cell infiltration and activity, enhancing antitumor immunity [ 147 ]. Metformin activates AMPK, which phosphorylates S195 of PD-L1, resulting in abnormal PD-L1 glycosylation [ 109 ].…”

Psychological distress and eustress in cancer and cancer treatment: Advances and perspectives

“…In a solid tumor model of stress-induced resistance to anti–PD-1 mAbs, β2-AR blockade up-regulated the ratio of effector CD8 + T cells to CD4 + T reg cells, decreased CD8 + TILs expressing PD-1, and thus reduced treatment resistance in the stressed mice ( 77 ). GR signaling has been shown to cause increased PD-L1 and decreased major histocompatibility complex I expression in pancreatic ductal adenocarcinoma models, thus promoting tumor immune escape and impairing the effects of anti–PD-1 treatment ( 78 ). GR blockade can induce an immunologically active TME to reverse the resistance to anti–PD-1 mAbs in mice caused by GC administration or social distress ( 22 , 78 ).…”

“…GR signaling has been shown to cause increased PD-L1 and decreased major histocompatibility complex I expression in pancreatic ductal adenocarcinoma models, thus promoting tumor immune escape and impairing the effects of anti–PD-1 treatment ( 78 ). GR blockade can induce an immunologically active TME to reverse the resistance to anti–PD-1 mAbs in mice caused by GC administration or social distress ( 22 , 78 ). Distress attenuated the antitumor effects of CpG-C, a novel Toll-like receptor-9 immunostimulatory agent, in metastatic tumor models by impairing CpG-C–induced NK-cell activity, which could be reversed by simultaneous inhibition of COX-2, as well as GR and β-AR signaling ( 33 ).…”