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Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer.
Clinical & Experimental Immunology ( IF 4.6 ) Pub Date : 2020-04-07 , DOI: 10.1111/cei.13436
S K Sureshbabu 1, 2 , D Chaukar 2, 3 , S V Chiplunkar 1, 2
Affiliation  

Hypoxia within the tumor microenvironment (TME) is a key factor contributing to immunosuppression in tumors, co‐relating with poor treatment outcome and decreased overall survival in advanced oral cancer (OC) patients. Vδ2 is a dominant subset of gamma delta T cells (γδT cells) present in the peripheral blood which exhibits potent anti‐tumor cytotoxicity and is evolving as a key player of anti‐cancer cellular therapy. However, the fate of γδT cells in hypoxic oral tumors remains elusive. In the present study, we compared the effect of hypoxia (1% O2) and normoxia (21% O2) on the expansion, proliferation, activation status, cytokine secretion and cytotoxicity of γδT cells isolated from OC patients and healthy individuals. Hypoxia‐exposed γδT cells exhibited reduced cytotoxicity against oral tumor cells. Our data demonstrated that hypoxia reduces the calcium efflux and the expression of degranulation marker CD107a in γδT cells, which explains the decreased anti‐tumor cytotoxicity of γδT cells observed under hypoxia. Hypoxia‐exposed γδT cells differentiated to γδT17 [γδ T cells that produce interleukin (IL)‐17] cells, which corroborated our observations of increased γδT17 cells observed in the oral tumors. Co‐culture of γδT cells with CD8 T cells in the presence of hypoxia showed that programmed cell death ligand 1 (PD‐L1)high γδT cells brought about apoptosis of programmed cell death 1 (PD‐1)high CD8 T cells which could be significantly reversed upon blocking PD‐1. Thus, future immunotherapeutic treatment modality for oral cancer may use a combined approach of blocking the PD‐1/PD‐L1 signaling and targeting hypoxia‐inducible factor 1α, which may help in reversing hypoxia‐induced immunosuppression.

中文翻译:

低氧调节口腔癌中γδT细胞的分化和抗肿瘤效应子功能。

肿瘤微环境(TME)内的缺氧是促成肿瘤免疫抑制的关键因素,与晚期口腔癌(OC)患者的不良治疗结果和降低的总生存率相关。Vδ2是外周血中存在的γ-δT细胞(γδT细胞)的主要子集,具有强大的抗肿瘤细胞毒性,并且正在发展成为抗癌细胞治疗的关键角色。然而,缺氧性口腔肿瘤中γδT细胞的命运仍然难以捉摸。在本研究中,我们比较了缺氧(1%O 2)和常氧(21%O 2)从OC患者和健康个体中分离出的γδT细胞的扩增,增殖,活化状态,细胞因子分泌和细胞毒性。缺氧暴露的γδT细胞对口腔肿瘤细胞的细胞毒性降低。我们的数据表明,低氧降低了γδT细胞的钙外流和脱颗粒标记CD107a的表达,这解释了低氧条件下γδT细胞的抗肿瘤细胞毒性降低。低氧暴露的γδT细胞分化为γδT17[产生白介素(IL)-17的γδT细胞]细胞,这证实了我们在口腔肿瘤中观察到的γδT17细胞增加的观察结果。在缺氧条件下将γδT细胞与CD8 T细胞共培养表明程序性细胞死亡配体1(PD-L1)γδT细胞引起程序性细胞死亡1(PD-1)CD8 T细胞凋亡,在阻断PD-1时可明显逆转。因此,未来针对口腔癌的免疫疗法可能会结合使用阻断PD-1 / PD-L1信号传导和靶向缺氧诱导因子1α的方法,这可能有助于逆转缺氧诱导的免疫抑制作用。
更新日期:2020-04-07
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