Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function.
Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function.
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DOI：
10.3389/fimmu.2017.01602
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发表时间：
2017
影响因子：
7.3
通讯作者：
Li K
中科院分区：
文献类型：
--
作者：
Liu CF;Min XY;Wang N;Wang JX;Ma N;Dong X;Zhang B;Wu W;Li ZF;Zhou W;Li K
补体受体3(CR3)在自然杀伤(NK)细胞上大量表达，但其在NK细胞依赖性肿瘤监测中的作用尚不清楚。在此，我们发现CR3是NK细胞功能的重要负性调节因子，对肿瘤的监视有负面影响。CR3基因缺失的小鼠(CD11b−/−小鼠)表现出更活跃的NK表型，并增强了NK依赖的肿瘤杀伤。在B16-Luc黑色素瘤诱导的肺肿瘤生长和转移模型中，与WT小鼠相比，CR3基因缺失的小鼠肿瘤生长和转移减少。此外，与转移CR3充足的NK细胞相比，适应性转移缺乏CR3的NK细胞可更有效地抑制肿瘤的生长和转移，提示CR3可能通过抑制NK细胞的功能而损害肿瘤的监视。体外分析表明，CR3与经典的CR3b(经典的CR3配体)结合对NK细胞的活性和效应功能(即直接杀伤肿瘤细胞、抗体依赖的NK介导的肿瘤杀伤)具有负面调节作用。细胞信号分析表明，iC3b刺激可激活NK细胞中含Src同源2区的肌醇-5-磷酸酶-1(SHIP-1)和JNK，抑制ERK，支持iC3b通过影响SHIP-1、JNK和ERK信号转导通路介导NK细胞功能的负性调节。因此，我们的研究结果表明，CR3在NK依赖的肿瘤监视功能失调中的作用是未知的，并提示iC3b/CR3信号是NK细胞功能的关键负调节因子，可能是保留癌症患者NK细胞功能和改进基于NK细胞的治疗的新靶点。
Complement receptor 3 (CR3) is expressed abundantly on natural killer (NK) cells; however, whether it plays roles in NK cell-dependent tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on tumor surveillance. Mice deficient in CR3 (CD11b−/− mice) exhibited a more activated NK phenotype and had enhanced NK-dependent tumor killing. In a B16-luc melanoma-induced lung tumor growth and metastasis model, mice deficient in CR3 had reduced tumor growth and metastases, compared with WT mice. In addition, adaptive transfer of NK cells lacking CR3 (into NK-deficient mice) mediated more efficient suppression of tumor growth and metastases, compared with the transfer of CR3 sufficient NK cells, suggesting that CR3 can impair tumor surveillance through suppression of NK cell function. In vitro analyses showed that engagement of CR3 with iC3b (classical CR3 ligand) on NK cells negatively regulated NK cell activity and effector functions (i.e. direct tumor cell killing, antibody-dependent NK-mediated tumor killing). Cell signaling analyses showed that iC3b stimulation caused activation of Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1) and JNK, and suppression of ERK in NK cells, supporting that iC3b mediates negative regulation of NK cell function through its effects on SHIP-1, JNK, and ERK signal transduction pathways. Thus, our findings demonstrate a previously unknown role for CR3 in dysregulation of NK-dependent tumor surveillance and suggest that the iC3b/CR3 signaling is a critical negative regulator of NK cell function and may represent a new target for preserving NK cell function in cancer patients and improving NK cell-based therapy.