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Down-regulation of HLA-B-associated transcript 3 impairs the tumoricidal effect of natural killer cells through promoting the T cell immunoglobulin and mucin domain-containing-3 signaling in a mouse head and neck squamous cell carcinoma model
Immunobiology ( IF 2.8 ) Pub Date : 2021-07-30 , DOI: 10.1016/j.imbio.2021.152127
Jiyong Yang 1 , Jun Xiang 1 , Meiling Zhu 1 , Yuman Zhao 1 , Lei Zhou 1 , Binbin Hu 1 , Cheng Wang 1
Affiliation  

Head and neck squamous cell carcinoma (HNSCC) arises from the malignant mucosal epithelium of the oral cavity, pharynx, and larynx. Natural killer (NK) cells are fundamental immune cells shaping the anti-HNSCC response. Elucidation of the regulatory mechanisms of NK cell activity is crucial for understanding anti-HNSCC immunity. In this study, we characterized the expression and function of HLA-B-associated transcript 3 (Bat3) in NK cells in a mouse HNSCC model. We found that Bat3 expression was down-regulated in HNSCC-infiltrating NK cells. SCC VII, the mouse HNSCC cell line used in this model, induced Bat3 downregulation through direct cell-to-cell contact. By applying lentivirus-mediated silencing of Bat3, we discovered that Bat3 knockdown impaired the tumoricidal effect of NK cells on SCC VII cells and Hepa1-6RAE1, a genetically modified liver cancer cell line. Furthermore, Bat3 knockdown resulted in a significant decrease in perforin, granzyme B, interferon-γ, and tumor necrosis factor-α in NK cells upon co-culture with SCC VII cells. Further investigations revealed that Bat3 knockdown promoted the binding of T cell immunoglobulin and mucin domain-containing-3 (Tim-3) to Fyn and thus activated the Tim-3 signaling. Blockade of Tim-3 with a neutralizing Tim-3 antibody counteracted the effect of Bat3 knockdown on NK cell cytotoxicity. Taken together, our data suggest that HNSCC might down-regulate Bat3 expression to augment Tim-3 signaling and ultimately suppress the tumoricidal activity of NK cells. This study unveils a novel mechanism by which HNSCC evades NK cell killing, and sheds light on designing novel anti-HNSCC immunotherapy targeting Bat3 and Tim-3 signaling.



中文翻译:

在小鼠头颈部鳞状细胞癌模型中,HLA-B 相关转录物 3 的下调通过促进 T 细胞免疫球蛋白和含有粘蛋白结构域的 3 信号传导损害自然杀伤细胞的杀肿瘤作用

头颈部鳞状细胞癌 (HNSCC) 起源于口腔、咽部和喉部的恶性黏膜上皮。自然杀伤 (NK) 细胞是形成抗 HNSCC 反应的基本免疫细胞。阐明 NK 细胞活性的调节机制对于了解抗 HNSCC 免疫至关重要。在这项研究中,我们在小鼠 HNSCC 模型中表征了 NK 细胞中 HLA-B 相关转录物 3 (Bat3) 的表达和功能。我们发现 Bat3 表达在 HNSCC 浸润 NK 细胞中下调。该模型中使用的小鼠 HNSCC 细胞系 SCC VII 通过直接的细胞间接触诱导 Bat3 下调。通过应用慢病毒介导的 Bat3 沉默,我们发现 Bat3 敲低削弱了 NK 细胞对 SCC VII 细胞和 Hepa1-6 RAE1的杀肿瘤作用,一种转基因肝癌细胞系。此外,在与 SCC VII 细胞共培养后,Bat3 敲低导致 NK 细胞中的穿孔素、颗粒酶 B、干扰素-γ 和肿瘤坏死因子-α 显着减少。进一步的研究表明,Bat3 敲低促进了 T 细胞免疫球蛋白和含有粘蛋白结构域 3 (Tim-3) 与 Fyn 的结合,从而激活了 Tim-3 信号传导。用中和 Tim-3 抗体阻断 Tim-3 抵消了 Bat3 敲低对 NK 细胞细胞毒性的影响。总之,我们的数据表明 HNSCC 可能下调 Bat3 表达以增强 Tim-3 信号传导并最终抑制 NK 细胞的杀肿瘤活性。这项研究揭示了 HNSCC 逃避 NK 细胞杀伤的新机制,

更新日期:2021-07-30
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