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CD70 反向信号增强了表达 CD27 的 B 细胞恶性肿瘤中 NK 细胞的功能和免疫监视。

CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies.

机构信息

Tumor Immunology, Department of Clinical Research, University of Bern, Bern, Switzerland.

Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; and.

出版信息

Blood. 2017 Jul 20;130(3):297-309. doi: 10.1182/blood-2016-12-756585. Epub 2017 May 11.

Abstract

The interaction of the tumor necrosis factor receptor (TNFR) CD27 with its ligand CD70 is an emerging target to treat cancer. CD27 signaling provides costimulatory signals to cytotoxic T cells but also increases the frequency of regulatory T cells. Similar to other TNFR ligands, CD70 has been shown to initiate intracellular signaling pathways (CD70 reverse signaling). CD27 is expressed on a majority of B-cell non-Hodgkin lymphoma, but its role in the immune control of lymphoma and leukemia is unknown. We therefore generated a cytoplasmic deletion mutant of CD27 (CD27-trunc) to study the role of CD70 reverse signaling in the immunosurveillance of B-cell malignancies in vivo. Expression of CD27-trunc on malignant cells increased the number of tumor-infiltrating interferon γ-producing natural killer (NK) cells. In contrast, the antitumoral T-cell response remained largely unchanged. CD70 reverse signaling in NK cells was mediated via the AKT signaling pathway and increased NK cell survival and effector function. The improved immune control by activated NK cells prolonged survival of CD27-trunc-expressing lymphoma-bearing mice. Finally, CD70 reverse signaling enhanced survival and effector function of human NK cells in a B-cell acute lymphoblastic leukemia xenotransplants model. Therefore, CD70 reverse signaling in NK cells contributes to the immune control of CD27-expressing B-cell lymphoma and leukemia.

摘要

肿瘤坏死因子受体(TNFR)CD27 与其配体 CD70 的相互作用是治疗癌症的一个新兴靶点。CD27 信号提供共刺激信号给细胞毒性 T 细胞,但也增加了调节性 T 细胞的频率。与其他 TNFR 配体类似,CD70 已被证明能启动细胞内信号通路(CD70 反向信号)。CD27 在大多数 B 细胞非霍奇金淋巴瘤上表达,但它在淋巴瘤和白血病的免疫控制中的作用尚不清楚。因此,我们生成了 CD27 的细胞质缺失突变体(CD27-trunc),以研究 CD70 反向信号在体内 B 细胞恶性肿瘤免疫监视中的作用。恶性细胞上 CD27-trunc 的表达增加了肿瘤浸润的产生干扰素 γ 的自然杀伤(NK)细胞的数量。相比之下,抗肿瘤 T 细胞反应基本保持不变。NK 细胞中的 CD70 反向信号是通过 AKT 信号通路介导的,增加了 NK 细胞的存活和效应功能。激活的 NK 细胞的改善免疫控制延长了表达 CD27-trunc 的淋巴瘤荷瘤小鼠的存活。最后,在 B 细胞急性淋巴细胞白血病异种移植模型中,CD70 反向信号增强了人 NK 细胞的存活和效应功能。因此,NK 细胞中的 CD70 反向信号有助于控制表达 CD27 的 B 细胞淋巴瘤和白血病。

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