Ionic immune suppression within the tumour microenvironment limits T cell effector function.
Ionic immune suppression within the tumour microenvironment limits T cell effector function.
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DOI：
10.1038/nature19364
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发表时间：
2016-09-22
期刊：
影响因子：
64.8
通讯作者：
Restifo, Nicholas P.
中科院分区：
文献类型：
--
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.
尽管被肿瘤特异性效应T细胞浸润，但肿瘤仍在进展。肿瘤含有细胞坏死区域，这与多种癌症的存活率低有关。在这里，我们表明，坏死释放的细胞内离子，钾，到细胞外液的小鼠和人类肿瘤引起深刻的抑制T细胞效应功能。我们发现，细胞外钾浓度[K+]e的升高会损害T细胞受体（TCR）驱动的Akt-mTOR磷酸化和效应程序，这种钾介导的Akt-mTOR信号传导和T细胞功能的抑制依赖于丝氨酸/苏氨酸磷酸酶PP 2A的活性。虽然[K+]e升高介导的抑制作用与质膜电位（Vm）的变化无关，但它确实需要细胞内钾（[K+]i）的增加。一致地，通过过表达钾通道Kv1.3的肿瘤特异性T细胞的离子重编程降低[K+]i并改善体外和体内效应器功能。因此，Kv1.3 T细胞过表达增强了荷黑色素瘤小鼠的肿瘤清除和存活。这些结果揭示了以前未描述的离子检查点阻断肿瘤内的T细胞功能，并确定了癌症免疫治疗的新策略。
Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which is associated with poor survival in a variety of cancers. Here, we show that necrosis releases an intracellular ion, potassium, into the extracellular fluid of mouse and human tumours causing profound suppression of T cell effector function. We find that elevations in the extracellular potassium concentration [K+]e act to impair T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes, this potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. While the suppressive effect mediated by elevated [K+]e is independent of changes in plasma membrane potential (Vm), it does require an increase in intracellular potassium ([K+]i). Concordantly, ionic reprogramming of tumour-specific T cells through overexpression of the potassium channel Kv1.3 lowers [K+]i and improves effector functions in vitro and in vivo. Consequently, Kv1.3 T cell overexpression enhances tumour clearance and survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint blocking T cell function within tumours and identify new strategies for cancer immunotherapy.
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影响因子：
29
作者：
Hla T;Dannenberg AJ
通讯作者：
Dannenberg AJ
影响因子：
15.3
作者：
Liu, Qing-Hua;Fleischmann, Bernd K;Hondowicz, Brian;Maier, Curtis C;Turka, Laurence A;Yui, Katsuyuki;Kotlikoff, Michael I;Wells, Andrew D;Freedman, Bruce D
通讯作者：
Freedman, Bruce D
DOI：
10.1085/jgp.27.1.37
发表时间：
1943-09-20
期刊：
The Journal of general physiology
影响因子：
--
作者：
Goldman DE
通讯作者：
Goldman DE
影响因子：
8.7
作者：
通讯作者：
--
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