Amino acids and RagD potentiate mTORC1 activation in CD8(+) T cells to confer antitumor immunity.
Amino acids and RagD potentiate mTORC1 activation in CD8(+) T cells to confer antitumor immunity.
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DOI：
10.1136/jitc-2020-002137
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发表时间：
2021-04
影响因子：
10.9
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Zhang Y;Hu H;Liu W;Yan SM;Li Y;Tan L;Chen Y;Liu J;Peng Z;Yuan Y;Huang W;Yu F;He X;Li B;Zhang H
在肿瘤微环境中，肿瘤细胞能够通过竞争必需营养素（包括氨基酸）来抑制抗肿瘤免疫。然而，氨基酸缺失是否会调节CD8+肿瘤浸润淋巴细胞（TILs）的活性尚不清楚。在这项研究中，我们评估了氨基酸和Rag复合物在调节哺乳动物CD8+ TILs中雷帕霉素靶蛋白1 （mTORC1）信号传导中的作用。我们发现Rag复合物，特别是RagD，对CD8+ t细胞抗肿瘤免疫至关重要。RagD的表达与CD8+ TILs在小鼠异种肿瘤移植和临床人结肠癌样本中的抗肿瘤反应呈正相关。在RagD缺乏的情况下，CD8+ T细胞变得更加功能失调，mTORC1信号的衰减和增殖和细胞因子分泌的减少证明了这一点。氨基酸维持ragd介导的mTORC1向溶酶体的易位，从而在CD8+ T细胞中实现最大的mTORC1活性。此外，肿瘤细胞氨基酸消耗掩盖了t细胞对亮氨酸（LEU）的有限获取，导致ragd依赖性mTORC1活性受损。最后，与抗程序性细胞死亡蛋白1抗体联合，补充LEU可提高MC38荷瘤小鼠体内t细胞免疫。我们的研究结果表明，RagD和下游mTORC1信号传递的氨基酸信号对于t细胞受体启动的抗肿瘤免疫至关重要。RagD和LEU在TILs中营养素mTORC1信号传导中的作用的表征可能为基于RagD及其上游途径的潜在治疗策略提供建议。
In the tumor microenvironment, tumor cells are able to suppress antitumor immunity by competing for essential nutrients, including amino acids. However, whether amino acid depletion modulates the activity of CD8+ tumor-infiltrating lymphocytes (TILs) is unclear. In this study, we evaluated the roles of amino acids and the Rag complex in regulating mammalian target of rapamycin complex 1 (mTORC1) signaling in CD8+ TILs. We discovered that the Rag complex, particularly RagD, was crucial for CD8+ T-cell antitumor immunity. RagD expression was positively correlated with the antitumor response of CD8+ TILs in both murine syngeneic tumor xenografts and clinical human colon cancer samples. On RagD deficiency, CD8+ T cells were rendered more dysfunctional, as demonstrated by attenuation of mTORC1 signaling and reductions in proliferation and cytokine secretion. Amino acids maintained RagD-mediated mTORC1 translocation to the lysosome, thereby achieving maximal mTORC1 activity in CD8+ T cells. Moreover, the limited T-cell access to leucine (LEU), overshadowed by tumor cell amino acid consumption, led to impaired RagD-dependent mTORC1 activity. Finally, combined with antiprogrammed cell death protein 1 antibody, LEU supplementation improved T-cell immunity in MC38 tumor-bearing mice in vivo. Our results revealed that robust signaling of amino acids by RagD and downstream mTORC1 signaling were crucial for T-cell receptor-initiated antitumor immunity. The characterization the role of RagD and LEU in nutrient mTORC1 signaling in TILs might suggest potential therapeutic strategies based on the manipulation of RagD and its upstream pathway.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM
影响因子：
32.4
作者：
Blagih, Julianna;Coulombe, Francois;Jones, Russell G.
通讯作者：
Jones, Russell G.
影响因子：
15.9
作者：
Kalaitzidis, Demetrios;Lee, Dongjun;Scadden, David T.
通讯作者：
Scadden, David T.
DOI：
10.1073/pnas.1620498114
发表时间：
2017-03-28
影响因子：
11.1
作者：
Mognol, Giuliana P.;Spreafico, Roberto;Trifari, Sara
通讯作者：
Trifari, Sara