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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–16.
Desiderio V, Papagerakis P, Tirino V, Zheng L, Matossian M, Prince ME, et al. Increased fucosylation has a pivotal role in invasive and metastatic properties of head and neck cancer stem cells. Oncotarget. 2014;6:71–84.
Lu X, Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res. 2010;16:5928–35.
Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–34.
Wu D, Wu P, Wu X, Ye J, Wang Z, Zhao S, et al. Ex vivo expanded human circulating Vdelta1 gammadeltaT cells exhibit favorable therapeutic potential for colon cancer. Oncoimmunology. 2015;4:e992749.
Kondo M, Sakuta K, Noguchi A, Ariyoshi N, Sato K, Sato S, et al. Zoledronate facilitates large-scale ex vivo expansion of functional gammadelta T cells from cancer patients for use in adoptive immunotherapy. Cytotherapy. 2008;10:842–56.
Lo Presti E, Dieli F, Meraviglia S. Tumor-Infiltrating gammadelta T lymphocytes: pathogenic role, clinical significance, and differential programming in the tumor microenvironment. Front Immunol. 2014;5:607.
Silva-Santos B, Serre K, Norell H. gammadelta T cells in cancer. Nat Rev Immunol. 2015;15:683–91.
Wu P, Wu D, Ni C, Ye J, Chen W, Hu G, et al. gammadeltaT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity. 2014;40:785–800.
Daley D, Zambirinis CP, Seifert L, Akkad N, Mohan N, Werba G, et al. gammadelta T cells support pancreatic oncogenesis by restraining alphabeta T cell activation. Cell. 2016;166:1485. e1415
Schorey JS, Bhatnagar S. Exosome function: from tumor immunology to pathogen biology. Traffic. 2008;9:871–81.
Peinado H, Lavotshkin S, Lyden D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol. 2011;21:139–46.
O’Loughlin AJ, Woffindale CA, Wood MJ. Exosomes and the emerging field of exosome-based gene therapy. Curr Gene Ther. 2012;12:262–74.
Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteom. 2010;73:1907–20.
Martins VR, Dias MS, Hainaut P. Tumor-cell-derived microvesicles as carriers of molecular information in cancer. Curr Opin Oncol. 2013;25:66–75.
King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.
Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70:9621–30.
Liu C, Yu S, Zinn K, Wang J, Zhang L, Jia Y, et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol. 2006;176:1375–85.
Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011;71:3792–801.
Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18:883–91.
Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringner M, et al. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci USA. 2013;110:7312–7.
Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, et al. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteom. 2010;9:1085–99.
Li L, Li C, Wang S, Wang Z, Jiang J, Wang W, et al. Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res. 2016;76:1770–80.
Li L, Zhang J, Diao W, Wang D, Wei Y, Zhang C, et al. MicroRNA-155 and MicroRNA-21 promote the expansion of functional myeloid-derived suppressor cells. J Immunol. 2014;192:1034–43.
Florcken A, Takvorian A, Singh A, Gerhardt A, Ostendorf BN, Dorken B, et al. Myeloid-derived suppressor cells in human peripheral blood: optimized quantification in healthy donors and patients with metastatic renal cell carcinoma. Immunol Lett. 2015;168:260–7.
Castella B, Foglietta M, Sciancalepore P, Rigoni M, Coscia M, Griggio V, et al. Anergic bone marrow Vgamma9Vdelta2 T cells as early and long-lasting markers of PD-1-targetable microenvironment-induced immune suppression in human myeloma. Oncoimmunology. 2015;4:e1047580.
Song M, Chen D, Lu B, Wang C, Zhang J, Huang L, et al. PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. PLoS One. 2013;8:e65821.
Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14:195–208.
Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med. 2001;7:297–303.
Rao Q, Zuo B, Lu Z, Gao X, You A, Wu C, et al. Tumor-derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro. Hepatology. 2016;64:456–72.
Plebanek MP, Angeloni NL, Vinokour E, Li J, Henkin A, Martinez-Marin D, et al. Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nat Commun. 2017;8:1319.
Gu X, Erb U, Buchler MW, Zoller M. Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice. Int J Cancer. 2015;136:E74–84.
Chen T, Guo J, Yang M, Zhu X, Cao X. Chemokine-containing exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine. J Immunol. 2011;186:2219–28.
Gao L, Wang L, Dai T, Jin K, Zhang Z, Wang S, et al. Tumor-derived exosomes antagonize innate antiviral immunity. Nat Immunol. 2018;19:233–45.
Ludwig S, Floros T, Theodoraki MN, Hong CS, Jackson EK, Lang S, et al. Suppression of lymphocyte functions by plasma exosomes correlates with disease activity in patients with head and neck cancer. Clin Cancer Res. 2017;23:4843–54.
Whiteside TL. Exosomes and tumor-mediated immune suppression. J Clin Invest. 2016;126:1216–23.
Liu Y, Gu Y, Cao X. The exosomes in tumor immunity. Oncoimmunology. 2015;4:e1027472.
Hasan MS, Bergmeier LA, Petrushkin H, Fortune F. Gamma Delta (gammadelta) T cells and their involvement in Behcet’s disease. J Immunol Res. 2015;2015:705831.
Chen W, Wang J, Shao C, Liu S, Yu Y, Wang Q, et al. Efficient induction of antitumor T cell immunity by exosomes derived from heat-shocked lymphoma cells. Eur J Immunol. 2006;36:1598–607.
Lv LH, Wan YL, Lin Y, Zhang W, Yang M, Li GL, et al. Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem. 2012;287:15874–85.
Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.
Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–90.
Ma S, Cheng Q, Cai Y, Gong H, Wu Y, Yu X, et al. IL-17A produced by gammadelta T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res. 2014;74:1969–82.
Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125:3356–64.
Zhu G, Tang Y, Geng N, Zheng M, Jiang J, Li L, et al. HIF-alpha/MIF and NF-kappaB/IL-6 axes contribute to the recruitment of CD11b+Gr-1+myeloid cells in hypoxic microenvironment of HNSCC. Neoplasia. 2014;16:168–79.
Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest. 2010;120:457–71.
Xiang X, Liu Y, Zhuang X, Zhang S, Michalek S, Taylor DD, et al. TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes. Am J Pathol. 2010;177:1606–10.
Kondo M, Izumi T, Fujieda N, Kondo A, Morishita T, Matsushita H. et al.Expansion of human peripheral blood gammadelta T cells using zoledronate. J Vis Exp. 2011;55:pii: 3182
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).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-018-0627-z
This article is cited by
-
Protein cargo in extracellular vesicles as the key mediator in the progression of cancer
Cell Communication and Signaling (2024)
-
γδ T cells and the PD-1/PD-L1 axis: a love–hate relationship in the tumor microenvironment
Journal of Translational Medicine (2024)
-
Roles of exosomes in immunotherapy for solid cancers
Cell Death & Disease (2024)
-
Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells
Cellular Oncology (2024)
-
Shedding Light on the Role of Exosomal PD-L1 (ExoPD-L1) in Cancer Progression: an Update
Cell Biochemistry and Biophysics (2024)