Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma
Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma
复制标题
肿瘤 EHF 预测抗 PD1 治疗胰腺导管腺癌的疗效
DOI：
10.1084/jem.20180749
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发表时间：
2019-03-01
影响因子：
15.3
通讯作者：
Hao, Jihui
中科院分区：
文献类型：
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作者：
Liu, Jing;Jiang, Wenna;Hao, Jihui
胰腺导管腺癌（PDAC）是一种高度免疫抑制性肿瘤，对单一检查点阻断疗法的应答率较低。ETS同源因子（EHF）是PDAC的肿瘤抑制因子。在这里，我们报告了EHF在胰腺癌免疫微环境编辑和抗PD 1治疗疗效预测中的新功能。我们的研究结果支持肿瘤EHF的缺陷诱导的调节性T（T reg）细胞和髓源性抑制细胞（MDSC）的积累和肿瘤浸润的CD 8 + T细胞的数量减少。EHF缺乏通过抑制肿瘤TGF-1和GM-CSF的分泌诱导T reg细胞和MDSC的转化和扩增。EHF通过直接与TGFB 1和CSF 2的启动子结合抑制其转录。携带EHF过表达肿瘤的小鼠对抗PD 1治疗的反应明显优于对照肿瘤的小鼠。我们的研究结果描述了PDAC中EHF缺陷的免疫抑制机制，并强调EHF过表达可能改善PDAC检查点免疫治疗。
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&bgr;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.