- Volume 14 Issue 1
DOI QR Code
Exosomes from Murine-derived GL26 Cells Promote Glioblastoma Tumor Growth by Reducing Number and Function of CD8+T Cells
- Liu, Zhi-Ming (Department of Neurosurgery, Zhongnan Hospital of Wuhan University) ;
- Wang, Yu-Bin (Wuhan University of Science and Technology) ;
- Yuan, Xian-Hou (Department of Neurosurgery, Zhongnan Hospital of Wuhan University)
- Published : 2013.01.31
Aim: Brain tumors almost universally have fatal outcomes; new therapeutics are desperately needed and will only come from improved understandins of glioma biology. Methods: Exosomes are endosomally derived 30~100 nm membranous vesicles released from many cell types. Examples from GL26 cells were here purified using density gradient ultracentrifugation and monitored for effects on GL26 tumor growth in C57BL/6j mice (H-2b). Lactate dehydrogenase release assays were used to detect the cytotoxic activity of CD8+T and NK cells. Percentages of immune cells producing intracellular cytokines were analyzed by FACS. Results: In this study, exosomes from murine-derived GL26 cells significantly promoted in vivo tumor growth in GL26-bearing B6 mice. Then we further analyzed the effects of the GL26 cells-derived exosomes on immune cells including CD8+T, CD4+T and NK cells. Inhibition of CD8+T cell cytotoxic activity was demonstrated by CD8+T cell depletion assays in vivo and LDH release assays in vitro. The treatment of mice with exosomes also led to a reduction in the percentages of CD8+T cells in splenocytes as determined by FACS analysis. Key features of CD8+T cell activity were inhibited, including release of IFN-gamma and granzyme B. There were no effects of exosomes on CD4+T cells and NK cells. Conclusion: Based on our data, for the first time we demonstrated that exosomes from murine derived GL26 cells promote the tumor growth by inhibition of CD8+T cells in vivo and thus may be a potential therapeutic target.
- Martin-Jaular L, Nakayasu ES, Ferrer M, et al (2011). Exosomes from Plasmodium yoelii-infected reticulocytes protect mice from lethal infections. PLoS One, 6, e26588. https://doi.org/10.1371/journal.pone.0026588
- Poutsiaka DD, Schroder EW, Taylor DD, et al (1985). Membrane vesicles shed by murine melanoma cells selectively inhibit the expression of Ia antigen by macrophages. J Immunol, 134, 138-44.
- Prado N, Marazuela EG, Segura E, et al (2008). Exosomes from bronchoalveolar fluid of tolerized mice prevent allergic reaction. J Immunol, 181, 1519-25. https://doi.org/10.4049/jimmunol.181.2.1519
- Rabinovich GA, Gabrilovich D, Sotomayor EM (2007). Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol, 25, 267-96. https://doi.org/10.1146/annurev.immunol.25.022106.141609
- Rivoltini L, Canese P, Huber V, et al (2005). Escape strategies and reasons for failure in the interaction between tumour cells and the immunesystem: how can we tilt the balance towards immune-mediated cancer control? Expert Opin Biol Ther, 5, 463-76. https://doi.org/10.1517/147125126.96.36.1993
- Rountree RB, Mandl SJ, Nachtwey JM, et al (2011). Exosome targeting of tumor antigens expressed by cancer vaccines can improve antigenimmunogenicity and therapeutic efficacy. Cancer Res, 71, 5235-44. https://doi.org/10.1158/0008-5472.CAN-10-4076
- Smyth MJ, Godfrey DI, Trapani JA (2001). A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol, 2, 293-9. https://doi.org/10.1038/86297
- Smyth MJ, Thia KY, Street SE, et al (2000). Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med, 191, 661-8. https://doi.org/10.1084/jem.191.4.661
- Taverna S, Flugy A, Saieva L, et al (2012). Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis. Int J Cancer, 130, 2033-43. https://doi.org/10.1002/ijc.26217
- Topfer K, Kempe S, Muller N, et al (2011). Tumor evasion from T cell surveillance. J Biomed Biotechnol, 2011, 918471.
- van Oijen M, Bins A, Elias S, et al (2004). On the role of melanoma-specific CD8+ T-cell immunity in disease progression of advanced-stagemelanoma patients. Clin Cancer Res, 10, 4754-60. https://doi.org/10.1158/1078-0432.CCR-04-0260
- Wilde S, Sommermeyer D, Leisegang M, et al (2012). Human antitumor CD8+ T cells producing Th1 polycytokines show superior antigen sensitivity and tumor recognition. J Immunol, 189, 598-605. https://doi.org/10.4049/jimmunol.1102165
- Yang AS, Lattime EC (2003). Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res, 63, 2150-7.
- Mallegol J, van Niel G, Heyman M (2005). Phenotypic and functional characterization of intestinal epithelial exosomes. Blood Cells Mol Dis, 35, 11-6. https://doi.org/10.1016/j.bcmd.2005.04.001
- Yang C, Ruffner MA, Kim SH, et al (2012). Plasma-derived MHC class II(+) exosomes from tumor-bearing mice suppress tumor antigen-specific immune responses. Eur J Immunol, 42, 1778-84. https://doi.org/10.1002/eji.201141978
- Zamarron BF, Chen W (2011). Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci, 7, 651-8.
- Zhong H, Yang Y, Ma S, et al (2011). Induction of a tumourspecific CTL response by exosomes isolated from heattreated malignant ascites of gastric cancer patients. Int J Hyperthermia, 27, 604-11. https://doi.org/10.3109/02656736.2011.564598
- Bacic D, Uravic M, Bacic R, et al (2011). Augmentation of regulatory T cells (CD4+CD25+Foxp3+) correlates with tumor stage in patients with colorectal cancer. Coll Antropol, 35, 65-8.
- Cho JA, Park H, Lim EH, et al (2011). Exosomes from ovarian cancer cells induce adipose tissue-derived mesenchymal stem cells to acquire the physical and functional characteristics of tumor-supporting myofibroblasts. Gynecol Oncol, 123, 379-86. https://doi.org/10.1016/j.ygyno.2011.08.005
- Clayton A, Al-Taei S, Webber J, et al (2011). Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J Immunol, 15, 676-83.
- Clayton A, Mitchell JP, Court J, et al (2007). Human tumorderived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res, 67, 7458-66. https://doi.org/10.1158/0008-5472.CAN-06-3456
- den Boer AT, van Mierlo GJ, Fransen MF, et al (2004). The tumoricidal activity of memory CD8+ T cells is hampered by persistent systemic antigen, but full functional capacity is regained in an antigen-free environment. J Immunol, 172, 6074-9. https://doi.org/10.4049/jimmunol.172.10.6074
- Diermayr S, Himmelreich H, Durovic B, et al (2008). NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood, 111, 1428-36.
- Friedman KM, Prieto PA, Devillier LE, et al (2012). Tumorspecific CD4+ melanoma tumor-infiltrating lymphocytes. J Immunother, 35, 400-8. https://doi.org/10.1097/CJI.0b013e31825898c5
- Hendrix A, Hume AN (2011). Exosome signaling in mammary gland development and cancer. Int J Dev Biol, 55, 879-87. https://doi.org/10.1387/ijdb.113391ah
- Hood JL, San RS, Wickline SA (2011). Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res, 71, 3792-801. https://doi.org/10.1158/0008-5472.CAN-10-4455
- Igney FH, Krammer PH (2002). Immnune escape of tumors: apoptosis resistance and tumor counterattack. J Leukoc Biol, 71, 907-20.
- Johann PD, Vaegler M, Gieseke F, et al (2010). Tumour stromal cells derived from paediatric malignancies display MSC-like properties and impair NK cell cytotoxicity. BMC Cancer, 21, 501.
- Kim R, Emi M, Tanabe K (2007). Cancer immunoediting from immune surveillance to immune escape. Immunology, 121, 1-14. https://doi.org/10.1111/j.1365-2567.2007.02587.x
- Kudo-Saito C, Shirako H, Takeuchi T, et al (2009). Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell, 15, 195-206. https://doi.org/10.1016/j.ccr.2009.01.023
- Liu C, Yu S, Zinn K, et al (2006). Murine Mammary Carcinoma Exosomes Promote Tumor Growth by Suppression of NK Cell Function. J Immunol, 176, 1375-85. https://doi.org/10.4049/jimmunol.176.3.1375
- Lotvall J, Valadi H (2007). Cell to cell signalling via exosomes through esRNA. Cell Adh Migr, 1, 156-8. https://doi.org/10.4161/cam.1.3.5114
- Lv LH, Wan YL, Lin Y, et al (2012). 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, 287, 15874-85. https://doi.org/10.1074/jbc.M112.340588
- Exosomes from breast cancer cells stimulate proliferation and inhibit apoptosis of CD133+ cancer cells in vitro vol.11, pp.1, 2014, https://doi.org/10.3892/mmr.2014.2749
- Impact of Allogenic and Autologous Transfusion on Immune Function in Patients with Tumors vol.15, pp.1, 2014, https://doi.org/10.7314/APJCP.2014.15.1.467
- Staurosporine Induced Apoptosis Rapidly Downregulates TDP-43 in Glioma Cells vol.15, pp.8, 2014, https://doi.org/10.7314/APJCP.2014.15.8.3575
- Extracellular vesicles shed by glioma cells: pathogenic role and clinical value vol.35, pp.9, 2014, https://doi.org/10.1007/s13277-014-2262-9
- Glioma-derived extracellular vesicles selectively suppress immune responses vol.18, pp.4, 2015, https://doi.org/10.1093/neuonc/nov170
- Biodistribution, Uptake and Effects Caused by Cancer-Derived Extracellular Vesicles vol.4, pp.1849-4544, 2015, https://doi.org/10.5772/60522
- From pathogenesis to clinical application: insights into exosomes as transfer vectors in cancer vol.35, pp.1, 2016, https://doi.org/10.1186/s13046-016-0429-5
- Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells vol.12, pp.1, 2017, https://doi.org/10.1371/journal.pone.0169932
- Functions of Cancer-Derived Extracellular Vesicles in Immunosuppression vol.65, pp.4, 2017, https://doi.org/10.1007/s00005-016-0453-3
- Exosomes: A Novel Strategy for Treatment and Prevention of Diseases vol.8, pp.1663-9812, 2017, https://doi.org/10.3389/fphar.2017.00300
- Cancer-derived extracellular vesicles: friend and foe of tumour immunosurveillance vol.373, pp.1737, 2018, https://doi.org/10.1098/rstb.2016.0481
- Exosomes in cancer: small vesicular transporters for cancer progression and metastasis, biomarkers in cancer therapeutics vol.6, pp.2167-8359, 2018, https://doi.org/10.7717/peerj.4763
- The potential diagnostic and prognostic role of extracellular vesicles in glioma: current status and future perspectives pp.1651-226X, 2019, https://doi.org/10.1080/0284186X.2018.1551621