Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma

Jing Liu, Wenna Jiang, Kaili Zhao, Hongwei Wang, Tianxing Zhou, Weiwei Bai, Xiuchao Wang, Tiansuo Zhao, Chongbiao Huang, Song Gao, Tai Qin, Wenwen Yu, Bo Yang, Xin Li, Danqi Fu, Wei Tan, Shengyu Yang, He Ren, Jihui Hao

Research output: Contribution to journalArticle

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFβ1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.

Original languageEnglish (US)
Pages (from-to)656-673
Number of pages18
JournalJournal of Experimental Medicine
Volume216
Issue number3
DOIs
StatePublished - Mar 1 2019

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Adenocarcinoma
Neoplasms
Therapeutics
Tumor Microenvironment
Granulocyte-Macrophage Colony-Stimulating Factor
Immunosuppressive Agents
Pancreatic Neoplasms
Immunotherapy
Transcription Factors
T-Lymphocytes
Myeloid-Derived Suppressor Cells

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Liu, Jing ; Jiang, Wenna ; Zhao, Kaili ; Wang, Hongwei ; Zhou, Tianxing ; Bai, Weiwei ; Wang, Xiuchao ; Zhao, Tiansuo ; Huang, Chongbiao ; Gao, Song ; Qin, Tai ; Yu, Wenwen ; Yang, Bo ; Li, Xin ; Fu, Danqi ; Tan, Wei ; Yang, Shengyu ; Ren, He ; Hao, Jihui. / Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma. In: Journal of Experimental Medicine. 2019 ; Vol. 216, No. 3. pp. 656-673.
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abstract = "Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFβ1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.",
author = "Jing Liu and Wenna Jiang and Kaili Zhao and Hongwei Wang and Tianxing Zhou and Weiwei Bai and Xiuchao Wang and Tiansuo Zhao and Chongbiao Huang and Song Gao and Tai Qin and Wenwen Yu and Bo Yang and Xin Li and Danqi Fu and Wei Tan and Shengyu Yang and He Ren and Jihui Hao",
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Liu, J, Jiang, W, Zhao, K, Wang, H, Zhou, T, Bai, W, Wang, X, Zhao, T, Huang, C, Gao, S, Qin, T, Yu, W, Yang, B, Li, X, Fu, D, Tan, W, Yang, S, Ren, H & Hao, J 2019, 'Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma', Journal of Experimental Medicine, vol. 216, no. 3, pp. 656-673. https://doi.org/10.1084/jem.20180749

Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma. / Liu, Jing; Jiang, Wenna; Zhao, Kaili; Wang, Hongwei; Zhou, Tianxing; Bai, Weiwei; Wang, Xiuchao; Zhao, Tiansuo; Huang, Chongbiao; Gao, Song; Qin, Tai; Yu, Wenwen; Yang, Bo; Li, Xin; Fu, Danqi; Tan, Wei; Yang, Shengyu; Ren, He; Hao, Jihui.

In: Journal of Experimental Medicine, Vol. 216, No. 3, 01.03.2019, p. 656-673.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma

AU - Liu, Jing

AU - Jiang, Wenna

AU - Zhao, Kaili

AU - Wang, Hongwei

AU - Zhou, Tianxing

AU - Bai, Weiwei

AU - Wang, Xiuchao

AU - Zhao, Tiansuo

AU - Huang, Chongbiao

AU - Gao, Song

AU - Qin, Tai

AU - Yu, Wenwen

AU - Yang, Bo

AU - Li, Xin

AU - Fu, Danqi

AU - Tan, Wei

AU - Yang, Shengyu

AU - Ren, He

AU - Hao, Jihui

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFβ1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.

AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFβ1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.

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