CIS is a potent checkpoint in NK cell-mediated tumor immunity
CIS is a potent checkpoint in NK cell-mediated tumor immunity
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DOI：
10.1038/ni.3470
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发表时间：
2016-07-01
影响因子：
30.5
通讯作者：
Huntington, Nicholas D.
中科院分区：
文献类型：
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作者：
Delconte, Rebecca B.;Kolesnik, Tatiana B.;Huntington, Nicholas D.
自然杀伤(NK)细胞对异常细胞的检测受激活和抑制配体以及IL-15等细胞因子信号的整合控制。我们发现细胞因子诱导的SH2蛋白(CIS，由CISH编码)是NK细胞IL-15信号的关键负调节因子。在IL-15刺激下，NK细胞可迅速诱导出CISH，缺失后的NK细胞对IL-15高度敏感，表现为增殖、存活、干扰素-γ的产生和对肿瘤的细胞毒作用增强。这与NK细胞中增强的JAK-STAT信号有关，在NK细胞中，CISH被删除。相应地，CIS与酪氨酸激酶JAK1相互作用，抑制其酶活性，并以JAK为靶点降解蛋白酶体。在体内，CISH(-/-)小鼠对黑色素瘤、前列腺癌和乳腺癌转移具有抵抗力，这是NK细胞活性的内在机制。我们的数据揭示了NK细胞介导的肿瘤免疫中一个有效的细胞内检查点，并提示了针对阻断CIS功能的新的癌症免疫疗法的可能性。
The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-gamma production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.