Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma.
Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma.
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作者：
Murakami S;Shahbazian D;Surana R;Zhang W;Chen H;Graham GT;White SM;Weiner LM;Yi C
胰腺导管腺癌（Pancreatic ductal adencarcinoma， PDAC）的特点是高度炎症和严重的免疫抑制。在这里，我们发现yes相关蛋白（Yap）是小鼠和人类PDAC中免疫抑制微环境的关键调节因子。在Kras:p53突变的胰腺导管细胞中，Yap驱动多种细胞因子/趋化因子的表达和分泌，从而促进髓源性抑制细胞（myeleloids -derived suppressor cells, MDSCs）在体内和体外的分化和积累。胰腺特异性敲除Yap或抗体介导的MDSCs缺失可促进巨噬细胞重编程、T细胞再激活、Kras突变肿瘤导管细胞凋亡和急性胰腺炎后胰腺再生。在原发性人类PDAC中，YAP表达水平与MDSC基因特征密切相关，YAP或MDSC相关基因的高表达可预测PDAC患者的生存率降低。这些结果揭示了YAP在PDAC发病机制中的多方面作用，并强调了它作为这种致命疾病的治疗靶点的前景。
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high degree of inflammation and profound immune suppression. Here we identify Yes-associated protein (Yap) as a critical regulator of the immunosuppressive microenvironment in both mouse and human PDAC. Within Kras:p53 mutant pancreatic ductal cells, Yap drives the expression and secretion of multiple cytokines/chemokines, which in turn promote the differentiation and accumulation of Myeloid-derived suppressor cells (MDSCs) both in vitro and in vivo. Pancreas-specific knockout of Yap or antibody-mediated depletion of MDSCs promoted macrophage reprogramming, reactivation of T cells, apoptosis of Kras mutant neoplastic ductal cells, and pancreatic regeneration after acute pancreatitis. In primary human PDAC, YAP expression levels strongly correlate with a MDSC gene signature, and high expression of YAP or MDSC-related genes predicts decreased survival in PDAC patients. These results reveal multifaceted roles YAP in PDAC pathogenesis and underscore its promise as a therapeutic target for this deadly disease.