Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 3, Pages 656-673Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20180749
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Funding
- National Natural Science Foundation of China [81525021, 81672431, 81672435, 81720108028, 81772633, 81702426, 81702427, 81572618, 81802432, 81802433, 81871968, 81871978]
- National Key Clinical Specialist Construction Programs of China [2013544]
- Key Program of Prevention and Treatment of Chronic Diseases of Tianjin [17ZXMFSY0010]
- Key Program of Public Health Bureau Foundation of Tianjin [15KG144]
- Science and Technology Development Fund of Tianjin Education Commission for Higher Education [2017KJ198]
- Foundation of Tianjin Medical University [2016KYZQ17]
- National Cancer Institute [R01 CA175741]
- Elsa U. Pardee Foundation
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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 TGF beta 1 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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