PI3K/AKT/mTOR通路
癌症研究
蛋白激酶B
免疫系统
克拉斯
肺癌
肿瘤微环境
生物
医学
癌症
信号转导
免疫学
细胞生物学
病理
内科学
结直肠癌
作者
Kristin J. Lastwika,Willie Wilson,Qing Kay Li,Jeffrey W. Norris,Haiying Xu,Sharon R. Ghazarian,Hiroshi Kitagawa,Shigeru Kawabata,Janis M. Taube,Sheng Yao,Linda N. Liu,Joell J. Gills,Phillip A. Dennis
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2016-01-14
卷期号:76 (2): 227-238
被引量:644
标识
DOI:10.1158/0008-5472.can-14-3362
摘要
Abstract Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT–mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT–mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells. Cancer Res; 76(2); 227–38. ©2015 AACR.
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