Chiplunkar Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Navi-Mumbai, India.
Homi Bhabha National Institute (HBNI), BARC Training School Complex, Anushakti Nagar, Mumbai, India.
Clin Exp Immunol. 2020 Jul;201(1):40-57. doi: 10.1111/cei.13436. Epub 2020 May 18.
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% O ) and normoxia (21% O ) 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) γδT cells brought about apoptosis of programmed cell death 1 (PD-1) 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.
肿瘤微环境（TME）中的缺氧是导致肿瘤免疫抑制的关键因素，与晚期口腔癌（OC）患者治疗效果差和总生存期缩短相关。Vδ2 是外周血中占主导地位的γδT 细胞亚群，具有强大的抗肿瘤细胞毒性作用，正在成为癌症细胞治疗的关键因素。然而，γδT 细胞在缺氧口腔肿瘤中的命运仍不清楚。在本研究中，我们比较了缺氧（1%O ）和常氧（21%O ）对 OC 患者和健康个体分离的γδT 细胞的扩增、增殖、激活状态、细胞因子分泌和细胞毒性的影响。暴露于缺氧环境下的γδT 细胞对口腔肿瘤细胞的细胞毒性降低。我们的数据表明，缺氧降低了 γδT 细胞的钙外流和脱颗粒标记物 CD107a 的表达，这解释了在缺氧条件下观察到的 γδT 细胞抗肿瘤细胞毒性降低的原因。暴露于缺氧环境下的γδT 细胞分化为 γδT17[产生白细胞介素（IL）-17 的 γδT 细胞]细胞，这与我们在口腔肿瘤中观察到的 γδT17 细胞增加的观察结果相符。在存在缺氧的情况下，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 细胞导致程序性细胞死亡 1（PD-1）CD8 T 细胞凋亡，而阻断 PD-1 可显著逆转这种情况。因此，口腔癌的未来免疫治疗方法可能采用联合阻断 PD-1/PD-L1 信号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。
