Inhibition of mTOR complex 1/p70 S6 kinase signaling elevates PD-L1 levels in human cancer cells through enhancing protein stabilization accompanied with enhanced β-TrCP degradation
Inhibition of mTOR complex 1/p70 S6 kinase signaling elevates PD-L1 levels in human cancer cells through enhancing protein stabilization accompanied with enhanced β-TrCP degradation
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DOI：
10.1038/s41388-019-0877-4
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发表时间：
2019-08-29
期刊：
影响因子：
8
通讯作者：
Sun, Shi-Yong
中科院分区：
文献类型：
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作者：
Deng, Liang;Qian, Guoqing;Sun, Shi-Yong
哺乳动物雷帕霉素靶点（mTOR）参与肿瘤发生的正调控已被充分证明，因此mTOR已成为一个有吸引力的癌症治疗靶点。尽管雷帕霉素及其类似物（rapalogs）已被fda批准用于治疗某些癌症，但针对mTOR的重大成功，特别是新一代mTOR激酶抑制剂，尚未取得有效治疗癌症的成功。因此，我们仍然需要对mTOR轴在癌症中的生物学特性有一个透彻的了解。现在认识到，癌细胞上的程序性死亡配体1 （PD-L1）表达是通过与免疫细胞上的程序性死亡配体1 （PD-1）相互作用促进免疫抑制和免疫逃逸的关键机制。本研究揭示了mTOR复合物1 (mTORC1)/p70 S6激酶（p70S6K）在PD-L1对癌细胞和组织的负调控中的作用。我们证明mTOR抑制剂、raptor敲低或p70S6K抑制剂对这一信号通路的破坏可提高某些肺癌和其他癌细胞系中PD-L1的水平。通过抑制mTORC1/p70S6K信号来升高PD-L1可能是由于抑制了13- trcp介导的PD-L1蛋白酶体降解，因为抑制mTORC1或p70S6K促进了β - trcp降解，同时增强了PD-L1蛋白的稳定性。我们目前的研究结果表明癌症中mTOR轴的复杂性，在针对该轴进行有效的癌症治疗时应考虑到这一点。我们的研究结果也为通过共同靶向mTORC1/p70S6K信号增强PD-1/ pd - l1靶向癌症免疫治疗提供了强有力的科学依据。
The involvement of mammalian target of rapamycin (mTOR) in the positive regulation of oncogenesis has been well documented and thus mTOR has emerged as an attractive cancer therapeutic target. Although rapamycin and its analogues (rapalogs) are FDA-approved for the treatment of certain cancers, major success in targeting mTOR, particularly with new generation mTOR kinase inhibitors, for the effective treatment of cancers has not been achieved. Hence, a thorough understanding of the biology of the mTOR axis in cancer is still needed. It is now recognized that programmed death-ligand 1 (PD-L1) expression on cancer cells is a critical mechanism contributing to immunosuppression and immune escape via interacting with program death-1 (PD-1) on immune cells. This study has revealed a previously undiscovered role of the mTOR complex 1 (mTORC1)/p70 S6 kinase (p70S6K) in the negative regulation of PD-L1 on cancer cells and tissues. We demonstrate that disruption of this signaling pathway with mTOR inhibitors, raptor knockdown or p70S6K inhibitors elevated PD-L1 levels in some lung and other cancer cell lines. Elevation of PD-L1 by inhibition of mTORC1/p70S6K signaling is likely due to suppression of 13-TrCP-mediated proteasomal degradation of PD-L1, because inhibition of either mTORC1 or p70S6K facilitated beta-TrCP degradation accompanied with enhanced PD-L1 protein stabilization. Our current findings indicate the complexity of the mTOR axis in cancer, which should be considered when targeting this axis for effective cancer treatment. Our findings also suggest a strong scientific rationale for enhancing PD-1/PD-L1-targeted cancer immunotherapy through co-targeting mTORC1/p70S6K signaling.