In vivo therapeutic effects of colorectal cancer cell-derived exosomes

Document Type: Original Article

Authors

1 Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran

2 Department of Microbiology and Immunology, School of Medicine, Arak University of Medical Sciences, Arak, Iran

3 Traditional and Complementary Medicine Research Center (TCMRC), Arak University of Medical Sciences, Arak, Iran

10.22038/ijbms.2020.46465.10730

Abstract

Objective(s): Exosomes are nano-sized structures with lipid bilayer membranes that can be secreted by cancer cells. They play an important role in the biology of the tumor extracellular matrix. Exosomes may contain and transfer tumor antigens to dendritic cells to trigger T cell-mediated anti-tumor immune responses.
Materials and Methods: BALB/c mice bearing CT26 colorectal cancer were treated subcutaneously with purified exosomes from analogous tumor cells. The mice were analyzed with respect to tumor size, survival, and anti-tumor immunity responses, including gene expression of cytokines and flowcytometry analysis of T lymphocytes.
Results: The rate of tumor size growth in the exosome-treated group significantly decreased (p <0.05), and the flow cytometry results showed a significant reduction in the spleen regulatory T cells (Tregs) count of the exosome-treated group, compared with the untreated group (P=0.02). Although the increase in the serum level of interferon-γ (IFN-γ) and the number of cytotoxic CD8 T lymphocytes (CTLs) in the spleen tissue was not significant (P>0.05), the gene expression of IFN-γ increased significantly (P=0.006).
Conclusion: The present results revealed that subcutaneous administration of tumor-derived exosomes could effectively lead to the inhibition of tumor progression by decreasing the number of Treg cells and up-regulation of the IFN-γ gene. Therefore, tumor-derived exosomes can be used as potential vaccines in cancer immunotherapy.

Keywords


1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-386.
2. Tickner JA, Urquhart AJ, Stephenson SA, Richard DJ, O’Byrne KJ. Functions and therapeutic roles of exosomes in cancer. Front Oncol 2014;4:127:1-8.
3. Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 2008;41:98-107.
4. Antonarakis ES, Small EJ, Petrylak DP, Quinn DI, Kibel AS, Chang NN et al. Antigen-specific CD8 lytic phenotype induced by sipuleucel-T in hormone-sensitive or castration-resistant prostate cancer and association with overall survival. Clin Cancer Res 2018;24:4662-4671.
5. McNeel DG, Bander NH, Beer TM, Drake CG, Fong L, Harrelson S et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of prostate carcinoma. J Immunother Cancer 2016;4:92-103.
6. Li SP, Lin ZX, Jiang XY, Yu XY. Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools. Acta Pharmacol Sin 2018;39:542-551.
7. Delcayre A, Estelles A, Sperinde J, Roulon T, Paz P, Aguilar B et al. Exosome display technology: applications to the development of new diagnostics and therapeutics. Blood Cells Mol Dis 2005;35:158-168.
8. Sun W, Luo JD, Jiang H, Duan DD. Tumor exosomes: a double-edged sword in cancer therapy. Acta Pharmacol Sin 2018;39:534-541.
9. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol 2009;11:1143-1149.
10. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654-659.
11. Wang J, Zheng Y, Zhao M. Exosome-based cancer therapy: Implication for targeting cancer stem cells. Front Pharmacol 2016;7:533-543.
12. Loira-Pastoriza C, Todoroff J, Vanbever R. Delivery strategies for sustained drug release in the lungs. Adv Drug Deliv Rev 2014;75:81-91.
13. 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.
14. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet 2002;360:295-305.
15. Romagnoli GG, Zelante BB, Toniolo PA, Migliori IK, Barbuto JA. Dendritic cell-derived exosomes may be a tool for cancer immunotherapy by converting tumor cells into immunogenic targets. Front Immunol 2014;5:692-696.
16. Crombet Ramos T, Rodríguez PC, Neninger Vinageras E, Garcia Verdecia B, Lage Davila A. CIMAvax EGF (EGF-P64K) vaccine for the treatment of non-small-cell lung cancer. Expert Rev Vaccines 2015;14:1303-1311.
17. André F, Schartz NE, Chaput N, Flament C, Raposo G, Amigorena S et al. Tumor-derived exosomes: a new source of tumor rejection antigens. Vaccine 2002;20 Suppl 4:A28-31.
18. Zhang H, Wang Y, Bai M, Wang J, Zhu K, Liu R et al. Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA. Cancer Sci 2018;109:629-641.
19. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 1998;4:594-600.
20. Shojapour M, Mosayebi G, Hajihossein R, Noorbakhsh F, Mokarizadeh A, Ghahremani MH. A simplified protocol for the purification of schwann cells and exosome isolation from C57BL/6 mice. Rep Biochem Mol Biol 2018;7:9-15.
21. Koga K, Matsumoto K, Akiyoshi T, Kubo M, Yamanaka N, Tasaki A et al. Purification, characterization and biological significance of tumor-derived exosomes. Anticancer Res 2005;25:3703-3707.
22. Chaput N, Théry C. Exosomes: immune properties and potential clinical implementations. Semin Immunopathol 2011;33:419-440.
23. Rodríguez M, Silva J, López-Alfonso A, López-Muñiz MB, Peña C, Domínguez G et al. Different exosome cargo from plasma/bronchoalveolar lavage in non-small-cell lung cancer. Genes Chromosomes Cancer 2014;53:713-724.
24. Cho JA, Yeo DJ, Son HY, Kim HW, Jung DS, Ko JK et al. Exosomes: a new delivery system for tumor antigens in cancer immunotherapy. Int J Cancer 2005;114:613-622.
25. Fan W, Tian XD, Huang E, Zhang JJ. Exosomes from CIITA-transfected CT26 cells enhance anti- tumor effects. Asian Pac J Cancer Prev 2013;14:987-991.
26. Vincent-Schneider H, Stumptner-Cuvelette P, Lankar D, Pain S, Raposo G, Benaroch P et al. Exosomes bearing HLA-DR1 molecules need dendritic cells to efficiently stimulate specific T cells. Int Immunol 2002;14:713-722.
27. Théry C, Duban L, Segura E, Véron P, Lantz O, Amigorena S. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol 2002;3:1156-1162.
28. Brossart P, Wirths S, Brugger W, Kanz L. Dendritic cells in cancer vaccines. Exp Hematol 2001;29:1247-1255.
29. Wang J, Yao Y, Wu J, Li G. Identification and analysis of exosomes secreted from macrophages extracted by different methods. Int J Clin Exp Pathol 2015;8:6135-6142.
30. Mignot G, Roux S, Thery C, Ségura E, Zitvogel L. Prospects for exosomes in immunotherapy of cancer. J Cell Mol Med 2006;10:376-388.