TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy.
TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy.
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DOI：
10.1172/jci.insight.167829
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发表时间：
2023-11-08
期刊：
影响因子：
8
通讯作者：
Powell, Jonathan D.
中科院分区：
文献类型：
--
作者：
Patel, Chirag H.;Yi, Dong;Koleini, Navid;Wang, Xiaoxu;Dunkerly-Eyring, Brittany L.;Wen, Jiayu;Ranek, Mark J.;Bartle, Laura M.;Henderson, Daniel B.;Sagert, Jason;Kass, David A.;Powell, Jonathan D.
MTORC 1整合来自免疫微环境的信号传导，以调节T细胞活化、分化和功能。结节性硬化症中的TSC 2紧密调节mTORC 1激活。缺乏TSC 2的CD 8 + T细胞具有组成性增强的mTORC 1活性并产生稳健的效应T细胞;然而，持续的mTORC 1活化阻止了长寿命记忆性CD 8 + T细胞的产生。在这里，我们表明，操纵TSC 2在Ser 1365有效地调节激活，但不是基础的mTORC 1信号在CD 8 + T细胞。与未受刺激的TSC 2-KO细胞不同，表达磷酸沉默突变体TSC 2-S1365 A（TSC 2-SA）的CD 8 + T细胞保留了正常的基础mTORC 1活性。PKC和T细胞受体（TCR）刺激诱导TSC 2 S1365磷酸化，SA突变可显著增加mTORC 1激活和T细胞效应功能。因此，SA CD 8 + T细胞显示出更大的效应子应答，同时保留了它们成为长寿记忆T细胞的能力。SA CD 8 + T细胞在缺氧和酸性条件下也显示出增强的效应子功能。在鼠和人实体瘤模型中，用作过继性细胞疗法的SA CD 8 + T细胞显示出比WT CD 8 + T细胞更大的抗肿瘤免疫力。这些发现揭示了调节T细胞中mTORC 1活性的上游机制。TSC 2-SA突变增强了T细胞效应子功能和长期持久性/记忆形成，支持了一种设计更好的CAR-T细胞治疗癌症的方法。
MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however, sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show that manipulating TSC2 at Ser1365 potently regulated activated but not basal mTORC1 signaling in CD8+ T cells. Unlike nonstimulated TSC2-KO cells, CD8+ T cells expressing a phosphosilencing mutant TSC2-S1365A (TSC2-SA) retained normal basal mTORC1 activity. PKC and T cell receptor (TCR) stimulation induced TSC2 S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and T cell effector function. Consequently, SA CD8+ T cells displayed greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also displayed enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, SA CD8+ T cells used as adoptive cell therapy displayed greater antitumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhanced both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.
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DOI：
10.1073/pnas.1404264111
发表时间：
2014-10-14
影响因子：
11.1
作者：
Shrestha, Sharad;Yang, Kai;Chi, Hongbo
通讯作者：
Chi, Hongbo
影响因子：
64.8
作者：
Araki, Koichi;Turner, Alexandra P.;Shaffer, Virginia Oliva;Gangappa, Shivaprakash;Keller, Susanne A.;Bachmann, Martin F.;Larsen, Christian P.;Ahmed, Rafi
通讯作者：
Ahmed, Rafi
DOI：
10.1038/nri3701
发表时间：
2014-07
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
29.7
作者：
Powell JD;Pollizzi KN;Heikamp EB;Horton MR
通讯作者：
Horton MR
影响因子：
3.5
作者：
Linke M;Fritsch SD;Sukhbaatar N;Hengstschläger M;Weichhart T
通讯作者：
Weichhart T