Skip to main content

Advertisement

SpringerLink
Log in

Natural immunosurveillance against spontaneous, autochthonous breast cancers revealed and enhanced by blockade of IL-13-mediated negative regulation

  • Short Communication
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Introduction

We and others previously observed immunosurveillance against transplantable tumors in mice, and enhancement thereof by blockade of negative regulation by T reg cells or the NKT-IL-13-myeloid cell-TGF-β regulatory circuit. However, it was unknown whether natural immunosurveillance inhibits growth of completely spontaneous autochthonous tumors, and whether it can be improved by inhibition of negative regulation.

Materials and methods

To examine the existence of T cell-mediated immunosurveillance against spontaneous tumors, BALB-neuT mice were treated with anti-CD4 and/or anti-CD8. A role for IL-13 in the suppression of immunosurveillance was investigated by treating mice with IL-13 inhibitor.

Results

We show that even spontaneous autochthonous breast carcinomas arising in Her-2/neu transgenic mice appear more quickly when the mice are depleted of T cells, evidence for T-cell mediated immunosurveillance slowing tumor growth. This immunosurveillance could be further enhanced by blockade of IL-13 (but not IL-4) which slowed the appearance of these autologous tumors compared to control antibody-treated mice.

Conclusion

Thus, even completely spontaneous, autochthonous breast cancers can be controlled in part by natural immunosurveillance, and blockade of negative regulation can improve this control.

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

References

  1. Agarwal A, Rani M, Saha GK, Valarmathi TM, Bahadur S, Mohanti BK, Das SN (2003) Disregulated expression of the Th2 cytokine gene in patients with intraoral squamous cell carcinoma. Immunol Invest 32:17

    Article  PubMed  CAS  Google Scholar 

  2. Ambrosino E, Spadaro M, Iezzi M, Curcio C, Forni G, Musiani P, Wei WZ, Cavallo F (2006) Immunosurveillance of Erbb2 carcinogenesis in transgenic mice is concealed by a dominant regulatory T-cell self-tolerance. Cancer Res 66:7734

    Article  PubMed  CAS  Google Scholar 

  3. Boggio K, Nicoletti G, Di Carlo E, Cavallo F, Landuzzi L, Melani C, Giovarelli M, Rossi I, Nanni P, De Giovanni C, Bouchard P, Wolf S, Modesti A, Musiani P, Lollini PL, Colombo MP, Forni G (1998) Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J Exp Med 188:589

    Article  PubMed  CAS  Google Scholar 

  4. Chang DH, Osman K, Connolly J, Kukreja A, Krasovsky J, Pack M, Hutchinson A, Geller M, Liu N, Annable R, Shay J, Kirchhoff K, Nishi N, Ando Y, Hayashi K, Hassoun H, Steinman RM, Dhodapkar MV (2005) Sustained expansion of NKT cells and antigen-specific T cells after injection of {alpha}-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med 201:1503

    Article  PubMed  CAS  Google Scholar 

  5. Crowe NY, Coquet JM, Berzins SP, Kyparissoudis K, Keating R, Pellicci DG, Hayakawa Y, Godfrey DI, Smyth MJ (2005) Differential antitumor immunity mediated by NKT cell subsets in vivo. J Exp Med 202:1279

    Article  PubMed  CAS  Google Scholar 

  6. Di Carlo E, Diodoro MG, Boggio K, Modesti A, Modesti M, Nanni P, Forni G, Musiani P (1999) Analysis of mammary carcinoma onset and progression in HER-2/neu oncogene transgenic mice reveals a lobular origin. Lab Invest 79:1261

    PubMed  CAS  Google Scholar 

  7. Di Carlo E, Rovero S, Boggio K, Quaglino E, Amici A, Smorlesi A, Forni G, Musiani P (2001) Inhibition of mammary carcinogenesis by systemic IL12 or p185neu DNA vaccination in Her-2/neu transgenic BALB/c mice. Clin Cancer Res 7(Suppl 3):830s

    Google Scholar 

  8. Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H, Henderson SL, O’Hara RM Jr., Beier DR, Turner KJ, Wood CR, Collins M (1998) The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1. J Immunol 161:2317

    PubMed  CAS  Google Scholar 

  9. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991

    Article  PubMed  CAS  Google Scholar 

  10. Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R, Bui JD, Diamond MS, Koebel CM, Arthur C, White JM, Schreiber RD (2005) A critical function for type I interferons in cancer immunoediting. Nat Immunol 6:722

    Article  PubMed  CAS  Google Scholar 

  11. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137

    Article  PubMed  CAS  Google Scholar 

  12. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329

    Article  PubMed  CAS  Google Scholar 

  13. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113:1490

    PubMed  CAS  Google Scholar 

  14. Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, von Blomberg BM, Scheper RJ, van der Vliet HJ, van den Eertwegh AJ, Roelvink M, Beijnen J, Zwierzina H, Pinedo HM (2002) A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 8:3702

    PubMed  CAS  Google Scholar 

  15. Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7:1118

    Article  PubMed  CAS  Google Scholar 

  16. Gunn GR, Zubair A, Peters C, Pan ZK, Wu TC, Paterson Y (2001) Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. J Immunol 167:6471

    PubMed  CAS  Google Scholar 

  17. Hayakawa Y, Rovero S, Forni G, Smyth MJ (2003) Alpha-galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. Proc Natl Acad Sci USA 100:9464

    Article  PubMed  CAS  Google Scholar 

  18. Ishikawa A, Motohashi S, Ishikawa E, Fuchida H, Higashino K, Otsuji M, Iizasa T, Nakayama T, Taniguchi M, Fujisawa T (2005) A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 11:1910

    Article  PubMed  CAS  Google Scholar 

  19. Kobayashi M, Kobayashi H, Pollard RB, Suzuki F (1998) A pathogenic role of Th2 cells and their cytokine products on the pulmonary metastasis of murine B16 melanoma. J Immunol 160:5869

    PubMed  CAS  Google Scholar 

  20. Nanni P, Landuzzi L, Nicoletti G, De Giovanni C, Rossi I, Croci S, Astolfi A, Iezzi M, Di Carlo E, Musiani P, Forni G, Lollini PL (2004) Immunoprevention of mammary carcinoma in HER-2/neu transgenic mice is IFN-gamma and B cell dependent. J Immunol 173:2288

    PubMed  CAS  Google Scholar 

  21. Nieda M, Okai M, Tazbirkova A, Lin H, Yamaura A, Ide K, Abraham R, Juji T, Macfarlane DJ, Nicol AJ (2004) Therapeutic activation of V alpha24+ V beta11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103:383

    Article  PubMed  CAS  Google Scholar 

  22. Park JM, Terabe M, van den Broeke LT, Donaldson DD, Berzofsky JA (2004) Unmasking immunosurveillance against a syngeneic colon cancer by elimination of CD4+ NKT regulatory cells and IL-13. Int J Cancer 114:80

    Article  Google Scholar 

  23. Qin Z, Blankenstein T (2004) A cancer immunosurveillance controversy. Nat Immunol 5:3

    Article  PubMed  CAS  Google Scholar 

  24. Schreiber RD, Old LJ, Hayday AC, Smyth MJ (2004) Response to ‘A cancer immunosurveillance controversy’. Nat Immunol 5:4

    Article  CAS  Google Scholar 

  25. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107

    Article  PubMed  CAS  Google Scholar 

  26. Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI (2000) Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 191:661

    Article  PubMed  CAS  Google Scholar 

  27. Street SE, Cretney E, Smyth MJ (2001) Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 97:192

    Article  PubMed  CAS  Google Scholar 

  28. Terabe M, Berzofsky JA (2004) Immunoregulatory T cells in tumor immunity. Curr Opin Immunol 16:157

    Article  PubMed  CAS  Google Scholar 

  29. Terabe M, Matsui S, Noben-Trauth N, Chen H, Watson C, Donaldson DD, Carbone DP, Paul WE, Berzofsky JA (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1:515

    Article  PubMed  CAS  Google Scholar 

  30. Terabe M, Matsui S, Park J-M, Mamura M, Noben-Trauth N, Donaldson DD, Chen W, Wahl SM, Ledbetter S, Pratt B, Letterio JJ, Paul WE, Berzofsky JA (2003) Transforming growth factor-b production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 198:1741

    Article  PubMed  CAS  Google Scholar 

  31. Terabe M, Park JM, Berzofsky JA (2003) Role of IL-13 in negative regulation of anti-tumor immunity. Cancer Immunol Immunother 53:79

    Article  PubMed  Google Scholar 

  32. Terabe M, Swann J, Ambrosino E, Sinha P, Takaku S, Hayakawa Y, Godrey DI, Ostrand-Rosenberg S, Smyth MJ, Berzofsky JA (2005) A nonclassical non-Va14Ja18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. J Exp Med 202:1627

    Article  PubMed  CAS  Google Scholar 

  33. Willimsky G, Blankenstein T (2005) Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437:141

    Article  PubMed  CAS  Google Scholar 

  34. Wilson SB, Delovitch TL (2003) Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat Rev Immunol 3:211

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Scott Abrams and Dr. Crystal Mackall for critical reading of the manuscript and helpful suggestions. This work was in part supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors declare that there is no financial conflict of interests.

Author information

Author notes

  1. Jong Myun Park

    Present address: Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA

  2. Debra D. Donaldson

    Present address: Millennium Pharmaceuticals, Inc., 35 Landsdowne St., Cambridge, MA, 02139, USA 

Authors and Affiliations

  1. Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10-Room 6B-12, 9000 Rockville Pk, Bethesda, MD, 20892-1578, USA 

    Jong Myun Park, Masaki Terabe & Jay A. Berzofsky

  2. Wyeth Research, Cambridge, MA, USA 

    Debra D. Donaldson

  3. Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy

    Guido Forni

Authors
  1. Jong Myun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masaki Terabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debra D. Donaldson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guido Forni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jay A. Berzofsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masaki Terabe.

Additional information

This work was in part supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, J.M., Terabe, M., Donaldson, D.D. et al. Natural immunosurveillance against spontaneous, autochthonous breast cancers revealed and enhanced by blockade of IL-13-mediated negative regulation. Cancer Immunol Immunother 57, 907–912 (2008). https://doi.org/10.1007/s00262-007-0414-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-007-0414-0

Keywords

Search

Navigation