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Ionic immune suppression within the tumour microenvironment limits T cell effector function

机译：肿瘤微环境中的离子免疫抑制限制了T细胞效应子的功能

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摘要

Tumours progress despite being infiltrated by tumour-specific effector T cells(1). Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers(2). Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K+](e)) impairs T cell receptor (TCR)driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A(3,4). Although the suppressive effect mediated by elevated [K+](e) is independent of changes in plasma membrane potential (V-m), it requires an increase in intracellular potassium ([K+](i)). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv(1.3) lowers [K+](i) and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy.
机译：尽管肿瘤特异性效应T细胞浸润了肿瘤，但肿瘤进展（1）。肿瘤包含细胞坏死区域，与多种癌症的低存活率相关（2）。在这里，我们显示坏死释放细胞内钾离子到小鼠和人类肿瘤的细胞外液中，导致对T细胞效应子功能的深刻抑制。细胞外钾浓度（[K +]（e））升高会损害T细胞受体（TCR）驱动的Akt-mTOR磷酸化和效应子程序。钾介导的对Akt-mTOR信号和T细胞功能的抑制取决于丝氨酸/苏氨酸磷酸酶PP2A（3,4）的活性。尽管由[K +]（e）升高介导的抑制作用与质膜电位（V-m）的变化无关，但它需要增加细胞内钾（[K +]（i））。因此，通过过表达钾通道Kv（1.3）来增加肿瘤特异性T细胞中的钾外排降低[K +]（i）并改善体外和体内的效应子功能，并增强荷瘤小鼠的肿瘤清除率和存活率。这些结果揭示了一种可阻断肿瘤中T细胞功能的离子检查点，并确定了潜在的癌症免疫疗法新策略。

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  • 来源
    《Nature》 |2016年第7621期|539-543|共5页
  • 作者

    Eil Robert; Vodnala Suman K.; Clever David; Klebanoff Christopher A.; Sukumar Madhusudhanan; Pan Jenny H.; Palmer Douglas C.; Gros Alena; Yamamoto Tori N.; Patel Shashank J.; Guittard Geoffrey C.; Yu Zhiya; Carbonaro Valentina; Okkenhaug Klaus; Schrump David S.; Linehan W. Marston; Roychoudhuri Rahul; Restifo Nicholas P.;

  • 作者单位

    NCI, NIH, Bethesda, MD 20892 USA|Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97239 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA|Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA|Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, C Natzaret 115-117, Barcelona 08035, Spain;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    Babraham Inst, Lab Lymphocyte Signalling & Dev, Cambridge CB22 3AT, England;

    Babraham Inst, Lab Lymphocyte Signalling & Dev, Cambridge CB22 3AT, England;

    NCI, NIH, Bethesda, MD 20892 USA;

    NCI, NIH, Bethesda, MD 20892 USA;

    Babraham Inst, Lab Lymphocyte Signalling & Dev, Cambridge CB22 3AT, England;

    NCI, NIH, Bethesda, MD 20892 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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