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Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes

Oncogene volume 38, pages 2830–2843 (2019)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant nos. 81672690, 81772900, 81872196, and 81302375) and the Department of Science and Technology of Sichuan Province (grant nos. 2015SZ0053 and 2017JQ0040).

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  1. These authors contributed equally to this work: Ling Li, Bangrong Cao

Authors and Affiliations

  1. 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

    Ling Li, Zhaohui Wang, Shaoxin Wang, Jian Jiang & Guiquan Zhu

  2. 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

    Bangrong Cao

  3. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China

    Xinhua Liang

  4. Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Shichuan, China

    Shun Lu & Jinyi Lang

  5. Department of Clinical Laboratory, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

    Huaichao Luo

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Correspondence to Jinyi Lang or Guiquan Zhu.

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Li, L., Cao, B., Liang, X. et al. Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes. Oncogene 38, 2830–2843 (2019). https://doi.org/10.1038/s41388-018-0627-z

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