Skip to main content

Advertisement

SpringerLink
Log in

Enhanced anti-tumor immunity by superantigen-pulsed dendritic cells

  • Original article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Staphylococcal enterotoxins A (SEA) and B (SEB) are classical models of superantigens (SAg), which induce potent T-cell-stimulating activity by forming complexes with MHC class II molecules on antigen-presenting cells. This large-scale activation of T-cells is accompanied by increased production of cytokines such as interferon-γ (IFN-γ). Additionally, as we previously reported, IFN-γ-producing CD8+ T cells act as “helper cells,” supporting the ability of dendritic cells to produce interleukin-12 (IL-12)p70. Here, we show that DC pulsed with SAg promote the enhancement of anti-tumor immunity. Murine bone marrow-derived dendritic cells (DC) were pulsed with OVA257–264 (SIINFEKL), which is an H-2Kb target epitope of EG7 [ovalbumin (OVA)-expressing EL4] cell lines, in the presence of SEA and SEB and were subcutaneously injected into naïve C57BL/6 mice. SAg plus OVA257–264-pulsed DC vaccine strongly enhanced peptide-specific CD8+ T cells exhibiting OVA257–264-specific cytotoxic activity and IFN-γ production, leading to the induction of protective immunity against EG7 tumors. Furthermore, cyclophosphamide (CY) added to SAg plus tumor-antigens (OVA257–264, tumor lysate, or TRP-2) pulsed DC immunization markedly enhanced tumor-specific T-cell expansion and had a significant therapeutic effect against various tumors (EG7, 2LL, and B16). Superantigens are potential candidates for enhancing tumor immunity in DC vaccines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. White J, Herman A, Pullen AM et al (1989) The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal depetion in neonatal mice. Cell 56:27–35

    Article  PubMed  CAS  Google Scholar 

  2. Li H, Liera A, Tsuchiya D et al (1998) Three-dimensional structure of the complex between a T cell receptor beta chain and the superantigen staphylococcal enterotoxin B. Immunity 9:807–816

    Article  PubMed  CAS  Google Scholar 

  3. Malchiodi EL, Eisenstein E, Fields BA et al (1995) Superantigen binding to a T cell receptor betachain of known three-dimensional structure. J Exp Med 182:1833–1845

    Article  PubMed  CAS  Google Scholar 

  4. Sundberg EJ, Li H, Liera AS et al (2002) Structures of two streptococcal superantigens bound to TCR beta chains reveal diversity in the architecture of T cell signaling complexs. Structure 10:687–699

    Article  PubMed  CAS  Google Scholar 

  5. Kotzin BL, Leung DYM, Kappler J, Marrack P (1993) Superantigen and their potential role in human disease. Adv Immunol 54:99–166

    Article  PubMed  CAS  Google Scholar 

  6. Webb SR, Gascoigne NRJ (1994) T-cell activation by superantigens. Curr Opin Immunol 6:467–475

    Article  PubMed  CAS  Google Scholar 

  7. Litton MJ, Sander B, Murphy E et al (1994) Early expression of cytokines in lymph nodes after treatment in vivo with Staphylococcus enterotoxin B. J Immunol Methods 175:47–58

    Article  PubMed  CAS  Google Scholar 

  8. Kawabe Y, Ochi A (1991) Programmed cell death and extrathymic reduction of V beta8+ CD4+ T cells in mice tolerant to Staphylococcal aureus enterotoxin B. Nature 349:245–248

    Article  PubMed  CAS  Google Scholar 

  9. Heeg K, Gaus H, Griese D, Bendig S, Miethke T, Wagner H (1995) Superantigen-reactive T cells that display an anergic phenotype in vivo appear functional in vivo. Int Immunol 7:105–114

    Article  PubMed  CAS  Google Scholar 

  10. Sundstedt A, Dohlsten M, Hedlund G, Hoiden I, Bjorklund M, Kalland T (1994) Superantigens anergize cytokine production but not cytotoxity in vivo. Immunology 82:117–125

    PubMed  CAS  Google Scholar 

  11. Bhardwaj N, Fried man SM, Cole BC, Nisanian AJ (1992) Cendritic cells are potent antigen-presenting cells for microbial superantigens. J Exp Med 175:267–273

    Article  PubMed  CAS  Google Scholar 

  12. Bhrardwaj N, Young JW, Nisanian AJ, Baggers J, Steinman RM (1993) Small amounts of superantigens, when presented on dendritic cells, are sufficient to initiatiate to T cellresponses. J Exp Med 178:633–642

    Article  Google Scholar 

  13. Gurunathan S, Stobie L, Prussin C et al (2001) Requirements for the maintenance of Th1 immunity in vivo following DNAvaccination: A potential immunoregulatory role for CD8+ T cells. J Immunol 16:1283–1289

    Google Scholar 

  14. Wang B, Norbury CC, Greenwood R, Bonnink JR, Yewdell Jw, Frelinger JA (2001) Multiple paths for activation of naïve CD8+ T cells: CD4-independent help. J Immunol 167:1283–1289

    PubMed  CAS  Google Scholar 

  15. Mailliard RB, Egawa S, Cai Q et al (2002) Complementary dendritic cell-activating function of CD8+ and CD4+ T cells: helper role of CD8+ T cells in the development of T helper type 1 responses. J Exp Med 195:473–483

    Article  PubMed  CAS  Google Scholar 

  16. Nakamura Y, Watchmaker P, Urban J et al (2007) Helper function of memory CD8+ T cells: heterologous CD8+ T cells support the induction of therapeutic cancer immunity. Cancer Res 67:10012–10018

    Article  PubMed  CAS  Google Scholar 

  17. Osada T, Clay TM, Woo CY, Morse MA, Lyerly HK (2006) Dendritic cell-based immunotherapy. Int Rev Immunol 25:377–413

    Article  PubMed  CAS  Google Scholar 

  18. Fazle Akbar SMF, Abe M, Yoshida O, Murakami H, Onji M (2006) Dendritic cell-based therapy as a multidisciplinary approach to cancer treatment: present limitations and future scopes. Curr Med Chem 13:3113–3119

    Article  PubMed  CAS  Google Scholar 

  19. Lutsiak MEC, Semnani RT, Pascalis RD, Kashmiri SVS, Schlom J, Sabzevari H (2005) Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105:2862–2868

    Article  PubMed  CAS  Google Scholar 

  20. Ito T, Seo N, Yagi H, Tsujimura K, Takigawa M, Tokura Y (2003) Alterations of immune functions in barrier disrupted skin by UVB irradiation. J Dermatol Sci 33:151–159

    Article  PubMed  CAS  Google Scholar 

  21. Nakamura Y, Suda T, Nagata T et al (2003) Induction of protective immunity to Listeria monocytogenes with dendritic cells retrovirally transduced with a cytotoxic T lymphocyte epitope minigene. Infect Immun 71:1748–1754

    Article  PubMed  CAS  Google Scholar 

  22. Enomoto N, Nagata T, Suda T et al (2007) Immunization with dendritic cells loaded with alpha-galactosylceramide at priming phase, but not at boosting phase, enhances cytotoxic T lymphocyte activity against infection by intracellular bacteria. FEMS Immunol Med Microbiol 51:350–362

    Article  PubMed  CAS  Google Scholar 

  23. Ozawa Y, Suda T, Nagata T et al (2009) Mucosal vaccine using CTL epitope-pulsed dendritic cells confers protection for intracellular pathogen. Am J Respir Cell Mol Biol 41:440–448

    Article  PubMed  CAS  Google Scholar 

  24. Kominsky SL, Torres BA, Hobeika AC, Lake FA, Johnson HM (2001) Superantigen enhanced protection against a weak tumor-specific melanoma antigen: implications for prophylactic vaccination against cancer. Int J Cancer 94:834–841

    Article  PubMed  CAS  Google Scholar 

  25. Muraille E, Trez DC, Pajak B, Brait M, Urbain J, Leo O (2002) T cell-dependent maturation of dendritic cells in response to bacterial superantigens. J Immunol 168:4352–4360

    PubMed  CAS  Google Scholar 

  26. Egwu CE, Li W, Yu C-R et al (2006) Interferone-γ induce regression of epithelial cell carcinoma: critical role of IRF-1 and ICSBP transcription factors. Oncogene 25:3670–3679

    Article  Google Scholar 

  27. Kortylewski M, Komyod W, Kauffmann M-E et al (2004) Interferone-γ-mediated growth regulation of melanoma cells: involvement of STAT1-dependent and STAT1-independent signals. J Invest Dermatol 122:414–422

    Article  PubMed  CAS  Google Scholar 

  28. He XZ, Wang L, Zhang YY (2008) An effective vaccine against colon cancer in mice: use of recombinant adenovirus interleukin-12 transduced dendritic cells. World J Gastroenterol 14:532–540

    Article  PubMed  CAS  Google Scholar 

  29. Iinuma H, Okinaga K, Fukushima R et al (2006) Superior protective and therapeutic effect of IL-12 and IL-18 gene-transduced dendritic neuroblastoma fusion cells on liver metastasis of murine neuroblastoma. J Immunol 176:3461–3469

    PubMed  CAS  Google Scholar 

  30. Kim CH, Hong MJ, Park SD et al (2006) Enhancement of anti-tumor immunity specific to murine glioma by vaccination with tumor cell lysate-pulsed dendritic cells engineered to produce interleukin-12. Cancer Immunol Immunother 55:1309–1319

    Article  PubMed  CAS  Google Scholar 

  31. Matsushita N, Shari AP-T, Martin LM, Riker AI (2008) Comparative methodologies of regulatory T cell depletion in a murine melanoma model. J Immunol Methods 333:167–179

    Article  PubMed  CAS  Google Scholar 

  32. Valzasina B, Piconese S, Guiducci C, Colombo MP (2006) Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25- lymphocytes is thymus and proliferation independent. Cancer Res 66:4488–4495

    Article  PubMed  CAS  Google Scholar 

  33. Zhou G, Drake GC, Levitsky IH (2006) Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107:628–636

    Article  PubMed  CAS  Google Scholar 

  34. Liu JY, Wu Y, Zhang XS et al (2007) Single administration of low dose cyclophosphamide augments the antitumor effect of dendritic cell vaccine. Cancer Immunol Immunother 56:1597–1604

    Article  PubMed  CAS  Google Scholar 

  35. Wirth S, Bille F, Koenig S et al (2002) Testing mouse mammary virus superantigen as adjuvant in cytotoxic T-lymphcyte responses against a melanoma tumor antigen. Int J Cancer 99:201–206

    Article  PubMed  CAS  Google Scholar 

  36. Cheng JD, Babb JS, Langer C et al (2004) Individualized patient dosing in phase I clinical trials: the role of escalation with overdose control in PNU-214936. J Clin Oncol 22:602–609

    Article  PubMed  CAS  Google Scholar 

  37. Fangming Xiu, Cai Z, Yang Y, Wang X, Wang J, Cao X (2007) Surface anchorage of superantigen SEA promotes induction of specific antitumor immune response by tumor-derived exosomes. J Mol Med 85:511–521

    Article  Google Scholar 

  38. Ren S, Terman DS, Bohach G et al (2004) Intrapleural staphylococcal superantigen induces resolution of malignant pleural effusions and and a survival benefit in non-small cell lung cancer. Chest 125:1529–1539

    Article  Google Scholar 

Download references

Acknowledgments

We thank Drs. T. Uchiyama and H. Kato (Tokyo Women's Medical University) for providing SEA used in preliminary experiments, K. Shibata for operating flow cytometry. This work was supported by grants-in-aid for scientific research from the Japanese Society for the Promotion of Science (grant 19590889 to Y.N.).

Conflict of interest

None of the authors has any financial relationships with commercial entities that have an interest in the subject of this manuscript.

Author information

Authors and Affiliations

  1. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

    Masato Kato, Yutaro Nakamura, Takafumi Suda, Yuichi Ozawa, Naoki Inui, Hirotoshi Nakamura & Kingo Chida

  2. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Naoki Inui

  3. Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Naohiro Seo

  4. Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Toshi Nagata

  5. Department of Infectious Diseases, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Yukio Koide

  6. Department of Surgery, Immunology, Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA

    Pawel Kalinski

Authors
  1. Masato Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yutaro Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takafumi Suda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuichi Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoki Inui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naohiro Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshi Nagata
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yukio Koide
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pawel Kalinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hirotoshi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kingo Chida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yutaro Nakamura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kato, M., Nakamura, Y., Suda, T. et al. Enhanced anti-tumor immunity by superantigen-pulsed dendritic cells. Cancer Immunol Immunother 60, 1029–1038 (2011). https://doi.org/10.1007/s00262-011-1015-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-011-1015-5

Keywords

Search

Navigation