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Staphylococcal enterotoxin B/texosomes as a candidate for breast cancer immunotherapy

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Tumor Biology

Abstract

A new recombinant construct made up of two components, texosomes (TEX) and staphylococcal enterotoxin B (SEB), showed cytostatic properties against several types of tumor cells in vitro. Here, we aimed to assess the construct’s antitumor immunogenicity in a murine tumor model. SEB was anchored onto purified texosomes and was used for immunization of mice before challenge with 4T1 cells. Tumor size, survival time, necrosis, metastasis rate, and the levels of IL-2, IL-4, IL-17, IL-12, TNF-α, and IFN-γ were measured. Immunization of the mice with TEX-SEB increased the stimulation index of splenocytes significantly compared with the PBS-treated mice (p < 0.01). In addition, there was a significant increase of TNF-α, IL-2, and IFN-γ secreted from isolated splenocytes of the mice immunized by either TEX-SEB, TEX + SEB, TEX, or SEB in comparison with PBS (p < 0.001, p < 0.001, and p < 0.05, respectively), whereas no significant change of IL-4 secretion was observed in any treated groups. Finding from tumor tissue homogenate testing showed that the level of IL-17 and IFN-γ among mice immunized with TEX-SEB was significantly lower than PBS-treated group (p < 0.05). IL-12, IL-4, and TNF-α levels were not significantly different from PBS- and TEX-SEB-immunized groups except in the SEB-immunized mice. Although TEX-SEB immunization relatively prolonged the survival of the mice, it had no inhibitory impact on tumor size. Pathologic manifestations showed the significant rise of necrosis after immunization with TEX-SEB compared to PBS (p < 0.01). Overall, our findings suggest that the presence of SEB rescues tumorigenesis effects of TEX making the construct an appropriate candidate for tumor immunotherapy.

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References

  1. Delirezh N, Moazzeni SM, Shokri F, Shokrgozar MA, Atri M, Kokhaei P. Autologous dendritic cells loaded with apoptotic tumor cells induce T cell-mediated immune responses against breast cancer in vitro. Cell Immunol. 2009;257:23–31.

    Article  CAS  PubMed  Google Scholar 

  2. Curigliano G, Spitaleri G, Dettori M, Locatelli M, Scarano E, Goldhirsch A. Vaccine immunotherapy in breast cancer treatment: promising, but still early. Expert Rev Anticancer Ther. 2007;7:1225–41.

    Article  CAS  PubMed  Google Scholar 

  3. Rieger J, Freichels H, Imberty A, Putaux JL, Delair T, Jérôme C, et al. Polyester nanoparticles presenting mannose residues: toward the development of new vaccine delivery systems combining biodegradability and targeting properties. Biomacromolecules. 2009;10:651–7.

    Article  CAS  PubMed  Google Scholar 

  4. Hosseini HM, Fooladi AA, Nourani MR, Ghanezadeh F. Role of exosome in infectious disease. Inflamm Allergy Drug Targets. 2012. [Epub ahead of print].

  5. Fooladi AA, Mahmoodzadeh Hosseini H. Biological functions of exosomes in the liver in health and disease. Hepat Mon. 2014;14:e13514.

    Google Scholar 

  6. Yang C, Robbins PD. The roles of tumor-derived exosomes in cancer pathogenesis. Clin Dev Immunol. 2011;2011:842849.

    PubMed  PubMed Central  Google Scholar 

  7. Wolfers J, Lozier A, Raposo G, Regnault A, Théry 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. Bu N, Wu H, Sun B, Zhang G, Zhan S, Zhang R, et al. Exosome-loaded dendritic cells elicit tumor-specific CD8+ cytotoxic T cells in patients with glioma. J Neurooncol. 2011;104:659–67.

    Article  CAS  PubMed  Google Scholar 

  10. Dai S, Zhou X, Wang B, Wang Q, Fu Y, Chen T, et al. Enhanced induction of dendritic cell maturation and HLA-A*0201-restricted CEA-specific CD8(+) CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells. J Mol Med (Berl). 2006;84:1067–76.

    Article  CAS  Google Scholar 

  11. Zhang Y, Luo CL, He BC, Zhang JM, Cheng G, Wu XH. Exosomes derived from IL-12-anchored renal cancer cells increase induction of specific antitumor response in vitro: a novel vaccine for renal cell carcinoma. Int J Oncol. 2010;36:133–40.

    PubMed  Google Scholar 

  12. Yang Y, Xiu F, Cai Z, Wang J, Wang Q, Fu Y, et al. Increased induction of antitumor response by exosomes derived from interleukin-2 gene-modified tumor cells. J Cancer Res Clin Oncol. 2007;133:389–99.

    Article  PubMed  Google Scholar 

  13. Cho JA, Lee YS, Kim SH, Ko JK, Kim CW. Mhc independent anti-tumor immune responses induced by HSP70-enriched exosomes generate tumor regression in murine models. Cancer Lett. 2009;275:256–65.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Xiu F, Cai Z, Yang Y, Wang X, Wang J, Cao X. Surface anchorage of superantigen sea promotes induction of specific antitumor immune response by tumor-derived exosomes. J Mol Med (Berl). 2007;85:511–21.

    Article  CAS  Google Scholar 

  17. Hosseini H, Imani Fooladi AA, Soleimanirad J, Nourani MR, Davaran S, Mahdavi M. Staphylococcal entorotoxin b anchored exosome induces apoptosis in negative esterogen receptor breast cancer cells. Tumour Biol. 2014;35(4):3699–707.

    Article  Google Scholar 

  18. Hosseini H, Ali Imani Fooladi A, Soleimanirad J, Reza Nourani M, Mahdavi M. Exosome/staphylococcal enterotoxin b, an anti tumor compound against pancreatic cancer. J BUON. 2014;19:440–8.

    Google Scholar 

  19. Hosseini H, Soleimanirad J, Mehdizadeh Aghdam E, Amin M, Imani Fooladi AA. Texosome-anchored superantigen triggers apoptosis in original ovarian cancer cells. Med Oncol. 2015;32:409.

    Article  Google Scholar 

  20. Fooladi AA, Sattari M, Hassan ZM, Mahdavi M, Azizi T, Horii A. In vivo induction of necrosis in mice fibrosarcoma via intravenous injection of type b staphylococcal enterotoxin. Biotechnol Lett. 2008;30:2053–9.

    Article  CAS  PubMed  Google Scholar 

  21. Fooladi AAI, Sattari M, Nourani MR. Study of t-cell stimulation and cytokine release induced by staphylococcal enterotoxin type b and monophosphoryl lipid a. Arch Med Sci. 2009;3:335–41.

    Google Scholar 

  22. McHugh RS, Nagarajan S, Wang YC, Sell KW, Selvaraj P. Protein transfer of glycosyl-phosphatidylinositol-b7-1 into tumor cell membranes: a novel approach to tumor immunotherapy. Cancer Res. 1999;59:2433–7.

    CAS  PubMed  Google Scholar 

  23. 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;35:158–68.

    Article  CAS  PubMed  Google Scholar 

  24. Schorey JS, Bhatnagar S. Exosome function: from tumor immunology to pathogen biology. Traffic. 2008;9:871–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human b-lymphocytes. J Biol Chem. 1998;273:20121–7.

    Article  CAS  PubMed  Google Scholar 

  26. Wubbolts R, Leckie RS, Veenhuizen PT, Schwarzmann G, Möbius W, Hoernschemeyer J, et al. Proteomic and biochemical analyses of human b cell-derived exosomes. Potential implications for their function and multivesicular body formation. J Biol Chem. 2003;278:10963–72.

    Article  CAS  PubMed  Google Scholar 

  27. Nagarajan S, Anderson M, Ahmed SN, Sell KW, Selvaraj P. Purification and optimization of functional reconstitution on the surface of leukemic cell lines of GPI-anchored Fc gamma receptor III. J Immunol Methods. 1995;184:241–51.

    Article  CAS  PubMed  Google Scholar 

  28. Fooladi AA, Sattari M, Reza Nourani M. Synergistic effects between staphylococcal enterotoxin type b and monophosphoryl lipid a against mouse fibrosarcoma. J BUON. 2010;15:340–7.

    Google Scholar 

  29. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hu M, Polyak K. Microenvironmental regulation of cancer development. Curr Opin Genet Dev. 2008;18:27–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Witz IP. The tumor microenvironment: the making of a paradigm. Cancer Microenviron. 2009;2 Suppl 1:9–17.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mbeunkui F, Johann DJ. Cancer and the tumor microenvironment: a review of an essential relationship. Cancer Chemother Pharmacol. 2009;63:571–82.

    Article  PubMed  Google Scholar 

  33. Sengupta N, MacFie TS, MacDonald TT, Pennington D, Silver AR. Cancer immunoediting and “spontaneous” tumor regression. Pathol Res Pract. 2010;206:1–8.

    Article  CAS  PubMed  Google Scholar 

  34. Li Z, Pradera F, Kammertoens T, Li B, Liu S, Qin Z. Cross-talk between T cells and innate immune cells is crucial for IFN-gamma-dependent tumor rejection. J Immunol. 2007;179:1568–76.

    Article  CAS  PubMed  Google Scholar 

  35. Goedegebuure PS, Lee KY, Matory YL, Peoples GE, Yoshino I, Eberlein TJ. Classification of CD4+ T helper cell clones in human melanoma. Cell Immunol. 1994;156:170–9.

    Article  CAS  PubMed  Google Scholar 

  36. Martín-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, et al. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for t(h)1 priming. Nat Immunol. 2004;5:1260–5.

    Article  PubMed  Google Scholar 

  37. Komita H, Homma S, Saotome H, Zeniya M, Ohno T, Toda G. Interferon-gamma produced by interleukin-12-activated tumor infiltrating CD8+T cells directly induces apoptosis of mouse hepatocellular carcinoma. J Hepatol. 2006;45:662–72.

    Article  CAS  PubMed  Google Scholar 

  38. Martini M, Testi MG, Pasetto M, Picchio MC, Innamorati G, Mazzocco M, et al. IFN-gamma-mediated upmodulation of MHC class I expression activates tumor-specific immune response in a mouse model of prostate cancer. Vaccine. 2010;28:3548–57.

    Article  CAS  PubMed  Google Scholar 

  39. He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol. 2010;184:2281–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ji Y, Zhang W. Th17 cells: positive or negative role in tumor? Cancer Immunol Immunother. 2010;59:979–87.

    Article  PubMed  Google Scholar 

  41. Pellegrini M, Mak TW, Ohashi PS. Fighting cancers from within: augmenting tumor immunity with cytokine therapy. Trends Pharmacol Sci. 2010;31:356–63.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Applied Microbiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.

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Authors and Affiliations

  1. Applied Microbiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Abbas Ali Imani Fooladi, Raheleh Halabian & Hamideh Mahmoodzadeh Hosseini

  2. Department of Immunology, Pasteur Institute of Iran, Tehran, Iran

    Mehdi Mahdavi

  3. Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mohsen Amin

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  1. Abbas Ali Imani Fooladi
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Correspondence to Hamideh Mahmoodzadeh Hosseini.

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Imani Fooladi, A.A., Halabian, R., Mahdavi, M. et al. Staphylococcal enterotoxin B/texosomes as a candidate for breast cancer immunotherapy. Tumor Biol. 37, 739–748 (2016). https://doi.org/10.1007/s13277-015-3877-1

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  • DOI: https://doi.org/10.1007/s13277-015-3877-1

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