Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Department of Basic Research, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Oncogene. 2019 Apr;38(15):2830-2843. doi: 10.1038/s41388-018-0627-z. Epub 2018 Dec 13.
γδ T cells are a unique lymphocyte population that have been reported to have either anti- or pro-tumoral functions in several cancer types, but the mechanisms are underinvestigated. Exosomes, initially considered to be cellular "garbage dumpsters," are now implicated in mediating interactions with the cellular environment. Hypoxia is a common feature of solid tumors and is believed to alter tumor-derived exosomes (TEXs), which mediate the hypoxic evolution of the tumor microenvironment in return. This study sought to investigate whether TEXs mediate the anti- and pro-tumoral equilibrium of γδ T cells under different oxygen pressures in the tumor microenvironment. We show that TEXs can alter the expansion and cytotoxicity of γδ T cells in an HSP70-dependent but dendritic cell-independent manner. The stimulating effects of normoxic TEXs on γδ T-cell activity were absent from hypoxic TEXs, which enhanced the suppressive effect of myeloid-derived suppressor cells (MDSCs) on γδ T cells through a miR-21/PTEN/PD-L1 regulation axis. Finally, the therapeutic outcome benefited from combined miR-21 and PD-L1 targeting in oral squamous cell carcinoma (OSCC)-bearing immunocompetent mice. We conclude that oxygen pressure in the tumor microenvironment orchestrates an anti- and pro-tumoral γδ T-cell equilibrium by altering TEX content, which subsequently regulates MDSC function in a miR-21/PTEN/PD-L1-axis-dependent manner. Our results should prompt further investigation into integrated exosomal miRNA inhibition and immune checkpoint inhibitor therapeutic modalities for patients with OSCC.
γδ T 细胞是一种独特的淋巴细胞群体，据报道，在几种癌症类型中，它们具有抗肿瘤或促肿瘤的功能，但这些机制尚未得到充分研究。外泌体最初被认为是细胞的“垃圾倾倒场”，现在被认为在介导与细胞环境的相互作用中起作用。缺氧是实体瘤的常见特征，据信它会改变肿瘤来源的外泌体（TEXs），而 TEXs 反过来又介导肿瘤微环境的缺氧演变。本研究旨在探讨 TEXs 是否在肿瘤微环境中不同氧压力下调节 γδ T 细胞的抗肿瘤和促肿瘤平衡。我们表明，TEXs 可以以 HSP70 依赖但树突状细胞独立的方式改变 γδ T 细胞的扩增和细胞毒性。来自低氧 TEXs 的正常氧 TEXs 对 γδ T 细胞活性的刺激作用消失，低氧 TEXs 通过 miR-21/PTEN/PD-L1 调节轴增强髓源抑制细胞（MDSCs）对 γδ T 细胞的抑制作用。最后，在具有免疫能力的口腔鳞状细胞癌（OSCC）荷瘤小鼠中，联合 miR-21 和 PD-L1 靶向治疗获益。我们得出结论，肿瘤微环境中的氧压通过改变 TEX 含量来协调抗肿瘤和促肿瘤的 γδ T 细胞平衡，从而随后通过 miR-21/PTEN/PD-L1 轴依赖性方式调节 MDSC 功能。我们的结果应该促使进一步研究针对 OSCC 患者的整合外泌体 miRNA 抑制和免疫检查点抑制剂治疗方式。
