KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma.
KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma.
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KRAS 突变诱导的 PD-L1 上调介导人肺腺癌的免疫逃逸
DOI：
10.1007/s00262-017-2005-z
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Chen N;Fang W;Lin Z;Peng P;Wang J;Zhan J;Hong S;Huang J;Liu L;Sheng J;Zhou T;Chen Y;Zhang H;Zhang L
据报道，PD-L1表达与遗传改变相关。PD-L1在非小细胞肺癌（NSCLC）中是否受突变型Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）的调控以及潜在的分子机制在很大程度上尚不清楚。在这项研究中，我们研究了PD-L1表达与KRAS突变之间的相关性以及PD-1/PD-L1阻断在KRAS突变肺腺癌中的功能意义。我们发现PD-L1表达与人肺腺癌细胞系和组织中的KRAS突变相关。KRAS突变通过p-ERK而非p-AKT信号转导上调PD-L1。我们还发现KRAS介导的PD-L1上调可诱导CD 3阳性T细胞的凋亡，而抗PD-1抗体（Pembrolizumab）或ERK抑制剂可逆转这一点。PD-1阻断剂或ERK抑制剂可恢复T细胞的抗肿瘤免疫力，降低KRAS突变NSCLC细胞在体外共培养体系中的存活率。然而，Pembrolizumab联合ERK抑制剂在共培养系统中没有显示出协同杀死肿瘤细胞的作用。我们的研究表明，KRAS突变可以通过p-ERK信号通路诱导肺腺癌中PD-L1的表达。阻断PD-1/PD-L1通路可能是KRAS突变型肺腺癌的一种有前景的治疗策略。本文的在线版本（doi：10.1007/s00262 - 017 - 2005-z）包含补充材料，可供授权用户使用。
It was reported that PD-L1 expression was correlated with genetic alterations. Whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-small-cell lung cancer (NSCLC) and the underlying molecular mechanism were largely unknown. In this study, we investigated the correlation between PD-L1 expression and KRAS mutation and the functional significance of PD-1/PD-L1 blockade in KRAS-mutant lung adenocarcinoma. We found that PD-L1 expression was associated with KRAS mutation both in the human lung adenocarcinoma cell lines and tissues. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling. We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by anti-PD-1 antibody (Pembrolizumab) or ERK inhibitor. PD-1 blocker or ERK inhibitor could recover the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, Pembrolizumab combined with ERK inhibitor did not show synergistic effect on killing tumor cells in co-culture system. Our study demonstrated that KRAS mutation could induce PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Blockade of PD-1/PD-L1 pathway may be a promising therapeutic strategy for human KRAS-mutant lung adenocarcinoma. The online version of this article (doi:10.1007/s00262-017-2005-z) contains supplementary material, which is available to authorized users.
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DOI：
10.1093/annonc/mdt205
发表时间：
2013-09
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Dearden S;Stevens J;Wu YL;Blowers D
通讯作者：
Blowers D
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
3.4
作者：
Cao, Christopher;Zhu, Zhi-Hua;He, Jianxing
通讯作者：
He, Jianxing
影响因子：
20.3
作者：
Kondo, Asaka;Yamashita, Taishi;Ogata, Kiyoyuki
通讯作者：
Ogata, Kiyoyuki
影响因子：
45.3
作者：
Lynch, Thomas J.;Bondarenko, Igor;Reck, Martin
通讯作者：
Reck, Martin