Gastric Cancer Mesenchymal Stem Cells Inhibit NK Cell Function through mTOR Signalling to Promote Tumour Growth.
Gastric Cancer Mesenchymal Stem Cells Inhibit NK Cell Function through mTOR Signalling to Promote Tumour Growth.
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DOI：
10.1155/2021/9989790
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发表时间：
2021
影响因子：
4.3
通讯作者：
Zhu W
中科院分区：
文献类型：
--
作者：
Guo S;Huang C;Han F;Chen B;Ding Y;Zhao Y;Chen Z;Wen S;Wang M;Shen B;Zhu W
自然杀伤(NK)细胞功能障碍在恶性肿瘤，特别是实体瘤中的报道越来越多。间充质干细胞(MSCs)具有多种功能，包括介导与癌症进展有关的免疫细胞衰竭。然而，胃癌来源的MSCs(胃癌间充质干细胞：GCMSCs)与NK细胞功能障碍之间的关系仍然知之甚少。在这项研究中，我们证明了GCMSCs通过释放可溶性因子有效地促进了NK细胞的耗竭。此外，NK细胞抗肿瘤作用的钝化与其功能障碍密切相关。GCMSC条件培养液阻止了荷瘤小鼠模型中NK细胞的频率和效应功能，从而促进了肿瘤的生长。从机制上讲，雷帕霉素(MTOR)信号的哺乳动物靶点在GCMSCs处理的NK细胞中受到抑制。mTOR是细胞代谢的关键调节因子，介导免疫细胞的功能。然而，无论有没有GCMSCs，检查点受体PD-1仍然存在于最低水平。研究结果表明，GCMSCs参与了功能紊乱的NK细胞，至少部分参与了对mTOR信号的抑制，这为基于NK细胞的癌症免疫治疗提供了潜在的方向。
The dysfunction of natural killer (NK) cells has been increasingly reported in malignancies, especially in solid tumours. Mesenchymal stem cells (MSCs) exhibit pleiotropic functions that include mediating immune cell exhaustion which is implicated in cancer progression. However, the association of MSCs derived from gastric cancer (gastric cancer mesenchymal stem cells: GCMSCs) with the dysfunction of NK cells remains poorly understood. In this study, we demonstrated that GCMSCs effectively contributed to the exhaustion of NK cells through the release of soluble factors. Furthermore, passivation of the antitumour effect in NK cells was closely associated with their dysfunctional state. The GCMSC-conditioned medium prevented the frequency and effector function of infiltrating NK cells in tumour-bearing mouse models, thus promoting tumour growth. Mechanistically, mammalian target of rapamycin (mTOR) signalling, a critical regulator of cellular metabolism that mediates the function of immune cells, was inhibited in NK cells treated with GCMSCs. However, the checkpoint receptor PD-1 was still present at minimal levels with or without GCMSCs. The study results revealed that GCMSCs contributed to dysfunctional NK cells involved at least partially in the inhibition of mTOR signalling, suggesting potential directions for NK cell-based cancer immunotherapy.
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