Nature2014-06-24 2:54 PM

 控制NK 细胞的抗转移活性 The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells

论文摘要 

这项研究介绍了E3泛素连接酶Cbl-b 作为先天“自然杀手”(NK)细胞中一个调控通道构成部分的一个以前不知道的作用,该通道“授权”这些细胞自发地拒绝癌症转移。小鼠Cbl-b的遗传丢失或其E3连接酶活性的失活,允许NK细胞去抑制多种原发肿瘤和远处肿瘤转移的生长。这种效应是通过TAM家族酪氨酸激酶受体的成员介导的,同时用一种小分子TAM抑制因子对野生型NK细胞进行处理,会产生针对转移性黑素瘤的治疗性NK细胞活性。这为对人类进行基于NK细胞的抗转移治疗提供了一个可能的方法,同时也解释了广泛使用的抗凝血药“杀鼠灵”的抗转移特性。

Abstract 

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a ‘pill’ that awakens the innate immune system to kill cancer metastases.

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