Inhibition of DCLK1 down-regulates PD-L1 expression through Hippo pathway in human pancreatic cancer
Inhibition of DCLK1 down-regulates PD-L1 expression through Hippo pathway in human pancreatic cancer
复制标题
抑制 DCLK1 通过 Hippo 通路下调人胰腺癌中 PD-L1 的表达
DOI：
10.1016/j.lfs.2019.117150
复制
发表时间：
2020
期刊：
影响因子：
6.1
通讯作者：
An Guangyu
中科院分区：
文献类型：
--
作者：
Yan Rui;Li JianJian;Zhou Ying;Yao Li;Sun Ruya;Xu Ying;Ge Yang;An Guangyu
与传统疗法相比，免疫疗法是最有前途的癌症治疗策略之一。作为关键的新兴免疫疗法之一，抗PD-1/PD-L1治疗为许多晚期癌症患者带来了生存益处。然而，在胰腺癌中，由于错配修复缺陷，基于免疫治疗的方法尚未取得有利的临床效果。因此，大多数胰腺肿瘤被认为是免疫静止肿瘤，对单检查点阻断疗法无反应。许多临床前和临床研究表明，阐明PD-1/PD-L1通路在胰腺癌中的调控机制仍然很重要。作为肿瘤干细胞的标志物，DCLK 1在多种人类肿瘤的发生发展中起着重要作用。近年来研究发现，DCLK 1与肿瘤细胞的EMT过程密切相关，同时也可作为胃肠道肿瘤的生物标志物，预测患者的预后。然而，DCLK 1在肿瘤微环境的免疫调节中发挥的作用仍然未知。因此，我们试图了解DCLK 1是否可以正向调节胰腺癌细胞中PD-L1的表达。此外，我们通过TCGA数据库分析检查DCLK 1是否与Hippo通路高度相关。我们发现DCLK 1通过影响Hippo通路中yes相关蛋白的相应表达水平来帮助调节PD-L1的表达水平。总的来说，我们的研究确定了DCLK 1是胰腺肿瘤中PD-L1表达的重要调节因子，并强调了DCLK 1在调节肿瘤免疫中的核心作用。
Immunotherapy is one of the most promising strategies for cancer, compared with traditional treatments. As one of the key emerging immunotherapies, anti-PD-1/PD-L1 treatment has brought survival benefits to many advanced cancer patients. However, in pancreatic cancer, immunotherapy-based approaches have not achieved a favorable clinical effect because of mismatch repair deficiencies. Therefore, the majority of pancreatic tumors are regarded as immune-quiescent tumors and non-responsive to single-checkpoint blockade therapies. Many preclinical and clinical studies suggest that it is still important to clarify the regulatory mechanism of the PD-1/PD-L1 pathway in pancreatic cancer. As a marker of cancer stem cells, DCLK1 has been found to play an important role in the occurrence and development of a plethora of human cancers. Recent researches have revealed that DCLK1 is closely related to EMT process of tumor cells, meanwhile, it could also be used as a biomarker in gastrointestinal tumors to predict the prognoses of patients. However, the role that DCLK1 plays in the immune regulation of tumor microenvironments remains unknown. Therefore, we sought to understand if DCLK1 could positively regulate the expression of PD-L1 in pancreatic cancer cells. Furthermore, we examined if DCLK1 highly correlated with the Hippo pathway through TCGA database analysis. We found that DCLK1 helped regulate the level of PD-L1 expression by affecting the corresponding expression level of yes-associated protein in the Hippo pathway. Collectively, our study identifies DCLK1 as an important regulator of PD-L1 expression in pancreatic tumor and highlights a central role of DCLK1 in the regulation of tumor immunity.