B7-H4-mediated immunoresistance is supressed by PI3K/Akt/mTOR pathway inhibitors
B7-H4-mediated immunoresistance is supressed by PI3K/Akt/mTOR pathway inhibitors
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B7-H4 介导的免疫抵抗被 PI3K/Akt/mTOR 通路抑制剂抑制
DOI：
10.1134/s0026893316060248
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发表时间：
2016-11-01
影响因子：
1.2
通讯作者：
Zhang, L.
中科院分区：
文献类型：
--
作者：
Zeng, S.;Song, H.;Zhang, L.
B7-H4在肿瘤免疫逃避中起重要作用。在以往的研究中，我们发现B7-H4可以易位到细胞核中，并且暴露于PI 3 K抑制剂Ly 294002影响B7-H4的亚细胞分布。在这项研究中，我们报告了PI 3 K/Akt通路在B7-H4亚细胞分布中的作用以及PI 3 K/Akt抑制剂对B7-H4介导的免疫抗性的影响。在使用渥曼青霉素的实验中，PI 3 K/Akt通路参与B7-H4亚细胞分布是明显的，而MDM 2抑制剂nutlin-3和mTOR抑制剂雷帕霉素用于剖析Akt下游的信号传导。渥曼青霉素和雷帕霉素对B7-H4亚细胞分布的影响相似。暴露于任何这些抑制剂降低膜B7-H4的水平，同时诱导其核积累，而暴露于nutlin-3对B7-H4亚细胞分布没有影响。在T细胞增殖测定中，渥曼青霉素和雷帕霉素均有效地抑制B7-H4 WT/293细胞介导的T细胞增殖，而对Mock/293细胞没有影响。PI 3 K/Akt/mTOR在B7-H4亚细胞分布中起作用，而MDM 2不参与B7-H4亚细胞分布。此外，我们发现渥曼青霉素和雷帕霉素通过调节B7-H4亚细胞分布来抑制B7-H4介导的肿瘤免疫抵抗。总之，这些结果表明，PI 3 K/Akt/mTOR抑制剂可用于旨在抑制免疫逃避的辅助治疗。
B7-H4 plays an important role in tumor immune evasion. In previous studies we have found that B7-H4 can translocate to the nucleus, and the exposure to PI3K inhibitor Ly294002 affects B7-H4 subcellular distribution. In this study we report the role of PI3K/Akt pathway in the B7-H4 subcellular distribution and the effect of PI3K/Akt inhibitors on B7-H4-mediated immunoresistance. The involvement of PI3K/Akt pathway in B7-H4 subcellular distribution was evident in experiments with wortmannin, while MDM2 inhibitor nutlin-3 and the mTOR inhibitor rapamycin were used to dissect the signaling downstream of Akt. Wortmannin and rapamycin demonstrated similar effects on B7-H4 subcellular distribution. Exposure to any of these inhibitors decreased levels of membrane B7-H4 while at the same time inducing its nuclear accumulation, while exposure to nutlin-3 had no effect on B7-H4 subcellular distribution. In the T cell proliferation assay, both wortmannin and rapamycin effectively inhibited B7-H4 WT/293 cells-mediated T cell proliferation while exerting no effect on Mock/293 cells. PI3K/Akt/mTOR plays a role in B7-H4 subcellular distribution, while MDM2 does not take part in it. Moreover, we show that wortmannin and rapamycin inhibit B7-H4-mediated tumor immunoresistance through regulating B7-H4 subcellular distribution. Taken together, these results suggest that PI3K/Akt/mTOR inhibitors might be used for adjuvant therapy aimed at inhibition of immune evasion.