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Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance
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 cel...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649069/ https://www.ncbi.nlm.nih.gov/pubmed/34873175 http://dx.doi.org/10.1038/s41467-021-27349-7 |
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author | 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 |
author_facet | 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 |
author_sort | Deng, Yalan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8649069 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86490692021-12-27 Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance 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 Nat Commun Article 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. Nature Publishing Group UK 2021-12-06 /pmc/articles/PMC8649069/ /pubmed/34873175 http://dx.doi.org/10.1038/s41467-021-27349-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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 Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance |
title | Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance |
title_full | Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance |
title_fullStr | Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance |
title_full_unstemmed | Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance |
title_short | Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance |
title_sort | glucocorticoid receptor regulates pd-l1 and mhc-i in pancreatic cancer cells to promote immune evasion and immunotherapy resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649069/ https://www.ncbi.nlm.nih.gov/pubmed/34873175 http://dx.doi.org/10.1038/s41467-021-27349-7 |
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