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Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice

Cancer Gene Therapy volume 13, pages 1002–1010 (2006)Cite this article

Abstract

The HER-2/Neu oncogene has been implicated in human and mouse breast cancer. Indeed, transgenic MMTV-neu mice expressing this oncogene from the mammary tumor virus long terminal repeat develop spontaneous mammary tumors and die within 1 year of life. We have expressed the class II transactivator (CIITA) and/or the costimulatory molecule CD80 (B7.1) in a mammary carcinoma cell line (MCNeuA) derived from these mice. Class II transactivator directs the expression of MHC class II and the machinery for antigen processing and presentation by this pathway. When injected into MMTV-neu mice, tumor cells expressing CD80 or CD80 and CIITA, were rejected completely. In addition, following the rejection of dual expressing cells, 75% of the mice were protected against the development of subsequent spontaneous tumors. Cells expressing only CD80 or CIITA were not as effective as antitumor vaccines in preventing the development of spontaneous tumors. Thus, converting cancer cells into antigen presenting cells could represent an effective immunotherapy for breast cancer.

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References

  1. Allison JP . CD28-B7 interactions in T-cell activation. Curr Opin Immunol 1994; 6: 414–419.

    Article  CAS  PubMed  Google Scholar 

  2. Bour-Jordan H, Blueston JA . CD28 function: a balance of co-stimulatory and regulatory signals. J Clin Immunol 2002; 22: 1–7.

    Article  CAS  PubMed  Google Scholar 

  3. Carreno BM, Collins M . The B7 family of ligands and its receptors: new pathways for co-stimulation and inhibition of immune responses. Annu Rev Immunol 2002; 20: 29–53.

    Article  CAS  PubMed  Google Scholar 

  4. Vesosky B, Hurwitz AA . Modulation of co-stimulation to enhance tumor immunity. Cancer Immunol Immunother 2003; 52: 663–669.

    Article  PubMed  Google Scholar 

  5. Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA et al. Co-stimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 1992; 71: 1093–1102.

    Article  CAS  PubMed  Google Scholar 

  6. Chen L, McGowan P, Ashe S, Johnston J, Li Y, Hellstrom I et al. Tumor immunogenicity determines the effect of B7 co-stimulation on T cell-mediated tumor immunity. J Exp Med 1994; 179: 523–532.

    Article  CAS  PubMed  Google Scholar 

  7. Chen L, McGowan P, Ashe S, Johnston JV, Hellstrom I, Hellstrom KE . B7-1/CD80-transduced tumor cells elicit better systemic immunity than wild-type tumor cells admixed with Corynebacterium parvum. Cancer Res 1994; 54: 5420–5423.

    CAS  PubMed  Google Scholar 

  8. Felzmann T, Ramsey WJ, Blaese RM . Anti-tumor immunity generated by tumor cells engineered to express B7-1 via retroviral or adenoviral gene transfer. Cancer Lett 1999; 135: 1–10.

    Article  CAS  PubMed  Google Scholar 

  9. Hurwitz AA, Townsend SE, Yu TF, Wallin JA, Allison JP . Enhancement of the anti-tumor immune response using a combination of interferon-gamma and B7 expression in an experimental mammary carcinoma. Int J Cancer 1998; 77: 107–113.

    Article  CAS  PubMed  Google Scholar 

  10. Martin-Fontecha A, Moro M, Crosti MC, Veglia F, Casorati G, Dellabona P . Vaccination with mouse mammary adenocarcinoma cells coexpressing B7-1 (CD80) and B7-2 (CD86) discloses the dominant effect of B7-1 in the induction of antitumor immunity. J Immunol 2000; 164: 698–704.

    Article  CAS  PubMed  Google Scholar 

  11. Takahashi T, Hirano N, Takahashi T, Chiba S, Yazaki Y, Hirai H . Immunogene therapy against mouse leukemia using B7 molecules. Cancer Gene Therapy 2000; 7: 144–150.

    Article  CAS  PubMed  Google Scholar 

  12. Townsend SE, Allison JP . Tumor rejection after direct co-stimulation of CD8+ T cells by B7-transfected melanoma cells. Science 1993; 259: 368–370.

    Article  CAS  PubMed  Google Scholar 

  13. Townsend SE, Su FW, Atherton JM, Allison JP . Specificity and longevity of antitumor immune responses induced by B7-transfected tumors. Cancer Res 1994; 54: 6477–6483.

    CAS  PubMed  Google Scholar 

  14. Vasilevko V, Ghochikyan A, Sadzikava N, Petrushina I, Tran M, Cohen EP et al. Immunization with a vaccine that combines the expression of MUC1 and B7 co-stimulatory molecules prolongs the survival of mice and delays the appearance of mouse mammary tumors. Clin Exp Metastasis 2003; 20: 489–498.

    Article  CAS  PubMed  Google Scholar 

  15. Yang G, Hellstrom KE, Hellstrom I, Chen L . Antitumor immunity elicited by tumor cells transfected with B7-2, a second ligand for CD28/CTLA-4 co-stimulatory molecules. J Immunol 1995; 154: 2794–2800.

    CAS  PubMed  Google Scholar 

  16. Ge NL, Ye SL, Zheng N, Sun RX, Liu YK, Tang ZY . Prevention of hepatocellular carcinoma in mice by IL-2 and B7-1 genes co-transfected liver cancer cell vaccines. World J Gastroenterol 2003; 9: 2182–2185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hull GW, McCurdy MA, Nasu Y, Bangma CH, Yang G, Shimura S et al. Prostate cancer gene therapy: comparison of adenovirus-mediated expression of interleukin 12 with interleukin 12 plus B7-1 for in situ gene therapy and gene-modified, cell-based vaccines. Clin Cancer Res 2000; 6: 4101–4109.

    CAS  PubMed  Google Scholar 

  18. Mukherjee S, Nelson D, Loh S, van Bruggen J, Palmer LJ, Leong C et al. The immune anti-tumor effects of GM-CSF and B7-1 gene transfection are enhanced by surgical debulking of tumor. Cancer Gene Therapy 2001; 8: 580–588.

    Article  CAS  PubMed  Google Scholar 

  19. Qian HN, Liu GZ, Cao SJ, Feng J, Ye X . The experimental study of ovarian carcinoma vaccine modified by human B7-1 and IFN-gamma genes. Int J Gynecol Cancer 2002; 12: 80–85.

    Article  PubMed  Google Scholar 

  20. Tatsumi T, Takehara T, Kanto T, Kazushita H, Ito A, Kasahara A et al. B7-1 (CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma. Hepatology 1999; 30: 422–429.

    Article  CAS  PubMed  Google Scholar 

  21. Jang YJ, Nam SY, Kim MS, Seong RH, Park YS, Chung YH et al. Simultaneous expression of allogenic class II MHC and B7.1 (CD80) molecules in A20 B-lymphoma cell line enhances tumor immunogenicity. Mol Cells 2002; 13: 130–136.

    CAS  PubMed  Google Scholar 

  22. Pulaski BA, Ostrand-Rosenberg S . Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res 1998; 58: 1486–1493.

    CAS  PubMed  Google Scholar 

  23. LeibundGut-Landmann S, Waldburger JM, Krawczyk M, Otten LA, Suter T, Fontana A et al. Mini-review: Specificity and expression of CIITA, the master regulator of MHC class II genes. Eur J Immunol 2004; 34: 1513–1525.

    Article  CAS  PubMed  Google Scholar 

  24. Ting JP, Trowsdale J . Genetic control of MHC class II expression. Cell 2002; 109: S21–S33.

    Article  CAS  PubMed  Google Scholar 

  25. Girdlestone J . Synergistic induction of HLA class I expression by RelA and CIITA. Blood 2000; 95: 3804–3808.

    CAS  PubMed  Google Scholar 

  26. Liu A, Takahashi M, Toba K, Zheng Z, Hashimoto S, Nikkuni K et al. Regulation of the expression of MHC class I and II by class II transactivator (CIITA) in hematopoietic cells. Hematol Oncol 1999; 17: 149–160.

    Article  PubMed  Google Scholar 

  27. Martin BK, Chin KC, Olsen JC, Skinner CA, Dey A, Ozato K et al. Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 1997; 6: 591–600.

    Article  CAS  PubMed  Google Scholar 

  28. Martin BK, Frelinger JG, Ting JP . Combination gene therapy with CD86 and the MHC class II transactivator in the control of lung tumor growth. J Immunol 1999; 162: 6663–6670.

    CAS  PubMed  Google Scholar 

  29. Armstrong TD, Clements VK, Martin BK, Ting JP, Ostrand-Rosenberg S . Major histocompatibility complex class II-transfected tumor cells present endogenous antigen and are potent inducers of tumor-specific immunity. Proc Natl Acad Sci USA 1997; 94: 6886–6891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Meazza R, Comes A, Orengo AM, Ferrini S, Accolla RS . Tumor rejection by gene transfer of the MHC class II transactivator in murine mammary adenocarcinoma cells. Eur J Immunol 2003; 33: 1183–1192.

    Article  CAS  PubMed  Google Scholar 

  31. Campbell MJ, Wollish WS, Lobo M, Esserman LJ . Epithelial and fibroblast cell lines derived from a spontaneous mammary carcinoma in a MMTV/neu transgenic mouse. In vitro Cell Dev Biol Anim 2002; 38: 326–333.

    Article  CAS  PubMed  Google Scholar 

  32. Morgenstern JP, Land H . Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res 1990; 18: 3587–3596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pear WS, Nolan GP, Scott ML, Baltimore D . Production of high-titer helper-free retroviruses by transient transfection. Proc Natl Acad Sci USA 1993; 90: 8392–8396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ . Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 1992; 89: 10578–10582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jabrane-Ferrat N, Nekrep N, Tosi G, Esserman LJ, Peterlin BM . Major histocompatibility complex class II transcriptional platform: assembly of nuclear factor Y and regulatory factor X (RFX) on DNA requires RFX5 dimers. Mol Cell Biol 2002; 22: 5616–5625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jabrane-Ferrat N, Bloom D, Wu A, Li L, Lo D, Sreedharan SP et al. Enhancement by vasoactive intestinal peptide of gamma-interferon production by antigen-stimulated type 1 helper T cells. FASEB J 1999; 13: 347–353.

    Article  CAS  PubMed  Google Scholar 

  37. Attal J, Theron MC, Houdebine LM . The optimal use of IRES (internal ribosome entry site) in expression vectors. Genet Anal 1999; 15: 161–165.

    Article  CAS  PubMed  Google Scholar 

  38. Attal J, Theron MC, Puissant C, Houdebine LM . Effect of intercistronic length on internal ribosome entry site (IRES) efficiency in bicistronic mRNA. Gene Expr 1999; 8: 299–309.

    CAS  PubMed  Google Scholar 

  39. Sisk TJ, Nickerson K, Kwok RP, Chang CH . Phosphorylation of class II transactivator regulates its interaction ability and transactivation function. Int Immunol 2003; 15: 1195–1205.

    Article  CAS  PubMed  Google Scholar 

  40. Van Wagoner NJ, O'Keefe GM, Benveniste EN . Kinase inhibitors abrogate IFN-gamma-induced class II transactivator and class II MHC gene expression in astroglioma cell lines. J Neuroimmunol 1998; 85: 174–185.

    Article  CAS  PubMed  Google Scholar 

  41. Disis ML, Grabstein KH, Sleath PR, Cheever MA . Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. Clin Cancer Res 1999; 5: 1289–1297.

    CAS  PubMed  Google Scholar 

  42. Dols A, Meijer SL, Smith II JW, Fox BA, Urba WJ . Allogeneic breast cancer cell vaccines. Clin Breast Cancer 2003; 3: S173–S180.

    Article  PubMed  Google Scholar 

  43. Dols A, Smith II JW, Meijer SL, Fox BA, Hu HM, Walker E et al. Vaccination of women with metastatic breast cancer, using a co-stimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. Hum Gene Ther 2003; 14: 1117–1123.

    Article  CAS  PubMed  Google Scholar 

  44. Emens LA, Armstrong D, Biedrzycki B, Davidson N, Davis-Sproul J, Fetting J et al. A phase I vaccine safety and chemotherapy dose-finding trial of an allogeneic GM-CSF-secreting breast cancer vaccine given in a specifically timed sequence with immunomodulatory doses of cyclophosphamide and doxorubicin. Hum Gene Ther 2004; 15: 313–337.

    Article  PubMed  Google Scholar 

  45. Jiang XP, Yang DC, Elliott RL, Head JF . Vaccination with a mixed vaccine of autogenous and allogeneic breast cancer cells and tumor associated antigens CA15-3, CEA and CA125 – results in immune and clinical responses in breast cancer patients. Cancer Biother Radiopharm 2000; 15: 495–505.

    Article  CAS  PubMed  Google Scholar 

  46. Knutson KL, Schiffman K, Cheever MA, Disis ML . Immunization of cancer patients with a HER-2/neu, HLA-A2 peptide, p369–377, results in short-lived peptide-specific immunity. Clin Cancer Res 2002; 8: 1014–1018.

    CAS  PubMed  Google Scholar 

  47. Peoples GE, Gurney JM, Hueman MT, Woll MM, Ryan GB, Storrer CE et al. Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients. J Clin Oncol 2005; 23: 7536–7545.

    Article  CAS  PubMed  Google Scholar 

  48. Schoof DD, Smith II JW, Disis ML, Brant-Zawadski P, Wood W, Doran T et al. Immunization of metastatic breast cancer patients with CD80-modified breast cancer cells and GM-CSF. Adv Exp Med Biol 1998; 451: 511–518.

    Article  CAS  PubMed  Google Scholar 

  49. Simons JW, Mikhak B . Ex-vivo gene therapy using cytokine-transduced tumor vaccines: molecular and clinical pharmacology. Semin Oncol 1998; 25: 661–676.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Gorazd Drozina, Lewis Lanier, Nada Nekrep and Giovanna Tosi for helpful comments and suggestions and Talal Al Saati for help with histology sections. This work was funded with grants from the Breast Cancer Research Program (#6KB-0116), the NIH (AI050770), the Treadwell Foundation, and the Breast Cancer Research Foundation.

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Authors and Affiliations

  1. Institut de Sciences et Technologies du Medicament de Toulouse, CNRS-Pierre Fabre, Toulouse, France

    N Jabrane-Ferrat

  2. Department of Surgery, University of California, San Francisco, CA, USA

    M J Campbell & L J Esserman

  3. Department of Medicine, Rosalind Russell Medical Research Center, University of California, San Francisco, CA, USA

    B M Peterlin

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Correspondence to B M Peterlin.

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Jabrane-Ferrat, N., Campbell, M., Esserman, L. et al. Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice. Cancer Gene Ther 13, 1002–1010 (2006). https://doi.org/10.1038/sj.cgt.7700974

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