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.
© 2019 Liu et al.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / mortality
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Adenocarcinoma / therapy*
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Aged
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Animals
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Biomarkers, Tumor / immunology
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Biomarkers, Tumor / metabolism
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CD8-Positive T-Lymphocytes
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Carcinoma, Pancreatic Ductal / metabolism
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Carcinoma, Pancreatic Ductal / mortality
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Carcinoma, Pancreatic Ductal / therapy*
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Female
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Gene Expression Regulation, Neoplastic
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Humans
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Male
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Middle Aged
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Molecular Targeted Therapy
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Myeloid-Derived Suppressor Cells / pathology
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / mortality
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Pancreatic Neoplasms / therapy*
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Transcription Factors / immunology
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Transcription Factors / metabolism*
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Transforming Growth Factor beta1 / genetics
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Tumor Microenvironment / immunology
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Xenograft Model Antitumor Assays
Substances
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Biomarkers, Tumor
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CSF2 protein, human
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EHF protein, human
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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TGFB1 protein, human
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Transcription Factors
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Transforming Growth Factor beta1
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Granulocyte-Macrophage Colony-Stimulating Factor