Tim-3 Hampers Tumor Surveillance of Liver-Resident and Conventional NK Cells by Disrupting PI3K Signaling
Tim-3 Hampers Tumor Surveillance of Liver-Resident and Conventional NK Cells by Disrupting PI3K Signaling
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Tim-3 通过破坏 PI3K 信号传导阻碍肝脏驻留细胞和传统 NK 细胞的肿瘤监测
DOI：
10.1158/0008-5472.can-19-2332
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发表时间：
2020-03-01
期刊：
影响因子：
11.2
通讯作者：
Ma, Chunhong
中科院分区：
文献类型：
--
作者：
Tan, Siyu;Xu, Yong;Ma, Chunhong
自然杀伤(NK)细胞在肝脏中丰富。除了常规的NK(CNK)细胞外，最近的研究发现了一种肝脏驻留的NK(LrNK)亚群，它约占肝脏NK细胞的一半，具有明显的发育、表型和功能特征。然而，LrNK细胞和CNK细胞是否以及如何单独参与肝细胞癌的发展仍不清楚。在此，我们报告了LrNK和CNK细胞在肝细胞癌中均显著减少。肿瘤浸润性LrNK细胞和CNK细胞的T细胞免疫球蛋白和粘蛋白结构域蛋白3(Tim-3)均显著上调，并抑制其细胞因子的分泌和细胞毒活性。机制上，磷脂酰丝氨酸(PtdSer)参与促进TIM-3的磷酸化，然后与PI3K p110竞争结合P85，抑制下游Akt/mTORC1信号，导致两个NK细胞亚群功能障碍。TIM-3阻断以NK细胞依赖的方式抑制肝癌的生长。这些研究首次报道了LrNK细胞在肝癌中的存在和功能障碍，并表明TIM-3介导的PI3K/mTORC1干扰导致了肿瘤浸润性CNK和LrNK细胞的功能障碍，为基于免疫检查点的靶向提供了新的策略。意义：Tim-3通过阻断自然杀伤细胞功能促进肝癌的生长。
Natural killer (NK) cells are enriched within the liver. Apart from conventional NK (cNK) cells, recent studies identified a liver-resident NK (LrNK) subset, which constitutes about half of hepatic NK cells and exhibits distinct developmental, phenotypic, and functional features. However, it remains unclear whether and how LrNK cells, as well as cNK cells, participate in the development of hepatocellular carcinoma (HCC) individually. Here, we report that both LrNK and cNK cells are significantly decreased in HCC. The T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) was significantly upregulated in both tumor-infiltrating LrNK and cNK cells and suppressed their cytokine secretion and cytotoxic activity. Mechanistically, phosphatidylserine (PtdSer) engagement promoted phosphorylation of Tim-3, which then competed with PI3K p110 to bind p85, inhibiting downstream Akt/mTORC1 signaling and resulting in malfunctioning of both NK-cell subsets. Tim-3 blockade retarded HCC growth in a NK-cell-dependent manner. These studies for the first time report the presence and dysfunction of LrNK cells in HCC and show that Tim-3-mediated PI3K/mTORC1 interference is responsible for the dysfunction of both tumor-infiltrating cNK and LrNK cells, providing a new strategy for immune checkpoint-based targeting.Significance: Tim-3 enhances hepatocellular carcinoma growth by blocking natural killer cell function.