Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma.
Jing LiuWenna JiangKaili ZhaoHongwei WangTianxing ZhouWeiwei BaiXiuchao WangTiansuo ZhaoChongbiao HuangSong GaoTai QinWenwen YuBo YangXin LiDanqi FuWei TanShengyu YangHe RenBaocun SunPublished in: The Journal of experimental medicine (2019)
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.
Keyphrases
- induced apoptosis
- transcription factor
- cell cycle arrest
- dna damage
- signaling pathway
- stem cells
- cell proliferation
- cell cycle
- replacement therapy
- crispr cas
- endoplasmic reticulum stress
- high glucose
- type diabetes
- cell death
- mesenchymal stem cells
- oxidative stress
- skeletal muscle
- adipose tissue
- insulin resistance
- cell therapy
- pi k akt