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Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor

Cancer Gene Therapy volume 9, pages 778–786 (2002)Cite this article

Abstract

The present study uses an in vivo murine tumor model expressing the human HER-2/neu antigen to evaluate the potential vaccine using dendritic cells (DCs) infected with adenovirus AdVHER-2. We first investigated whether infected DCs (DCHER-2) engineered to express HER-2/neu could induce HER-2/neu-specific immune responses. Our data showed that (i) AdVHER2-infected DCHER-2 expressed HER-2/neu by Western blot and flow cytometric analysis, and (ii) vaccination of mice with DCHER-2 induced HER-2/neu-specific cytotoxic T-lymphocyte (CTL) responses, but protected only 25% of vaccinated mice from challenge of 3×105 MCA26/HER-2 tumor cells. Further, to enhance the efficacy of DCHER-2 vaccine, we coinfected DCs with both AdVHER-2 and AdVTNF-α. The infected DCs (DCHER-2/TNF-α) displayed the expression of both HER-2/neu and TNF-α by flow cytometric and ELISA analysis. We next investigated whether DCHER-2/TNF-α could induce stronger HER-2/neu-specific immune responses. We found that DCHER-2/TNF-α displayed up-regulation of immunologically important CD40, CD86, and ICAM-I molecules compared with DCHER-2, indicating that the former ones are more mature forms of DCs. Vaccination of DCHER-2/TNF-α induced stronger allogeneic T-cell proliferation and 36% enhanced HER-2/neu-specific T-cell responses in vitro than DCHER-2 cells. More importantly, it stimulated the significant anti–HER-2/neu immunity in vivo, which protected 8/8 mice from challenge of 3×105 MCA26/HER-2 tumor cells. Therefore, DCs genetically engineered to express both the tumor antigen and cytokines such as TNF-α as an immunoadjuvant are likely to represent a new direction in DC vaccine of cancer.

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References

  1. Coussens L, Yang-Feng TL, Liao YC et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene Science 1985 230: 1132–1139

    Article  CAS  PubMed  Google Scholar 

  2. Slamon DJ, Godolphin W, Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer Science 1989 244: 707–712

    Article  CAS  PubMed  Google Scholar 

  3. Ishikawa T, Kobayashi M, Mai M et al. Amplification of the c-erbB-2 (HER-2/neu) gene in gastric cancer cells Am J Pathol 1997 151: 761–768

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Paterson MC, Dietrich KD, Danyluk J et al. Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer Cancer Res 1991 51: 556–567

    CAS  PubMed  Google Scholar 

  5. Andrulis IL, Bull SB, Blackstein ME et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group J Clin Oncol 1998 16: 1340–1349

    Article  CAS  PubMed  Google Scholar 

  6. Ioannides CG, Whiteside TL . T cell recognition of human tumors: implications for molecular immunotherapy of cancer Clin Immunol Immunopathol 1993 66: 91–106

    Article  CAS  PubMed  Google Scholar 

  7. Disis ML, Pupa SM, Gralow JR et al. High titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer J Clin Oncol 1997 15: 3363–3367

    Article  CAS  PubMed  Google Scholar 

  8. Disis ML, Grabstein KH, Sleath PR et al. 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 

  9. Zaks TZ, Rosenberg SA . Immunization with a peptide epitope (p369–377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+ tumors Cancer Res 1998 58: 4902–4908

    CAS  PubMed  Google Scholar 

  10. Nagata Y, Furugen R, Hiasa A et al. Peptides derived from a wild-type murine protooncogene c-erbB-2/HER2/neu can induce CTL and tumor suppression in syngeneic hosts J Immunol 1997 159: 1336–1343

    CAS  PubMed  Google Scholar 

  11. Weiner LM . Monoclonal antibody therapy of cancer Semin Oncol 1999 26: 43–51

    CAS  PubMed  Google Scholar 

  12. Chen Y, Hu D, Eling DJ et al. DNA vaccines encoding full-length or truncated Neu induce protective immunity against Neu-expressing mammary tumors Cancer Res 1998 58: 1965–1971

    CAS  PubMed  Google Scholar 

  13. Wei WZ, Shi WP, Galy A et al. Protection against mammary tumor growth by vaccination with full-length, modified human ErbB-2 DNA Int J Cancer 1999 81: 748–754

    Article  CAS  PubMed  Google Scholar 

  14. Foy TM, Bannink J, Sutherland RA et al. Vaccination with HER-2/neu DNA or protein subunits protects against growth of a HER-2/neu-expressing murine tumor Vaccine 2001 19: 2598–2606

    Article  CAS  PubMed  Google Scholar 

  15. Gabrilovich DI, Corak J, Ciernik IF et al. Decreased antigen presentation by dendritic cells in patients with breast cancer Clin Cancer Res 1997 3: 483–490

    CAS  PubMed  Google Scholar 

  16. Troy AJ, Summers KL, Davidson PJ et al. Minimal recruitment and activation of dendritic cells within renal cell carcinoma Clin Cancer Res 1998 4: 585–593

    CAS  PubMed  Google Scholar 

  17. Chaux P, Favre N, Martin M et al. Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats Int J Cancer 1997 72: 619–624

    Article  CAS  PubMed  Google Scholar 

  18. Nestle FO, Alijagic S, Gilliet M et al. Vaccination of melanoma patients with peptide or tumor lysate-pulsed dendritic cells Nat Med 1998 4: 328–332

    Article  CAS  PubMed  Google Scholar 

  19. Dhodapkar MV, Steinman RM, Sapp M et al. Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells J Clin Invest 1999 104: 173–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cella M, Sallusto F, Lanzavecchia A . Origin, maturation and antigen presenting function of dendritic cells Curr Opin Immunol 1997 9: 10–16

    Article  CAS  PubMed  Google Scholar 

  21. Pardoll D . Cancer vaccines Nat Med 1998 4: 525–530

    Article  CAS  PubMed  Google Scholar 

  22. Eggert A, Schreurs M, Boerman O et al. Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration Cancer Res 1999 59: 3340–3345

    CAS  PubMed  Google Scholar 

  23. Ribas A, Butterfield L, McBride W et al. Genetic immunization for the melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine dendritic cells Cancer Res 1997 57: 2865–2869

    CAS  PubMed  Google Scholar 

  24. Butterfield L, Jilani S, Chakraborty N et al. Generation of melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-1 adenovirus J Immunol 1998 161: 5607–5613

    CAS  PubMed  Google Scholar 

  25. Lapointe R, Royal R, Reeves M et al. Retrovirally transduced human dendritic cells can generate T cells recognizing multiple MHC class I and class II epitopes from the melanoma antigen glycoprotein 100 J Immunol 2001 167: 4758–4764

    Article  CAS  PubMed  Google Scholar 

  26. Labeur M, Roters B, Pers B et al. Generation of tumor immunity by bone marrow-derived dendritic cells correlates with dendritic cell maturation stage J Immunol 1999 162: 168–175

    CAS  PubMed  Google Scholar 

  27. Zhang W, Chen Z, Li F et al. TNF-transgene-expressing dendritic cells undergo augmented cellular maturation and induce more robust T cell activation and antitumor immunity than dendritic cells generated in recombinant TNF Immunology 2002 In press

  28. Wright P, Braun R, Babiuk L et al. Adenovirus-mediated TNF-α gene transfer induces significant tumor regression in mice Cancer Biother Radiopharm 1999 14: 49–57

    Article  CAS  PubMed  Google Scholar 

  29. Xiang J, Moyana T . Regression of engineered tumor cells secreting cytokines is related to a shift in host cytokine profile from type 2 to type 1 J Interferon Cytokine Res 2000 20: 349–354

    Article  CAS  PubMed  Google Scholar 

  30. Inaba K, Young J, Steiman R . Direct activation of CD8 cytotoxic T lymphocytes by dendritic cells J Exp Med 1987 166: 182–194

    Article  CAS  PubMed  Google Scholar 

  31. Andrechek E, Hardy W, Siegel P et al. Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis Proc Natl Acad Sci USA 2000 97: 3444–3449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tuting T, Wilson CC, Martin DM et al. Autologous human monocyte-derived dendritic cells genetically modified to express melanoma antigens elicit primary cytotoxic T cell responses in vitro: enhancement by cotransfection of genes encoding the Th1-biasing cytokines IL-12 and IFN-α J Immunol 1998 160: 1139–1147

    CAS  PubMed  Google Scholar 

  33. Nishioka Y, Hirao M, Robbins PD et al. Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express interleukin 12 Cancer Res 1999 59: 4035–4041

    CAS  PubMed  Google Scholar 

  34. Curiel-Lewandrowski C, Mahnke K, Labeur M et al. Transfection of immature murine bone marrow-derived dendritic cells with the granulocyte-macrophage colony-stimulating factor gene potently enhances their in vivo antigen-presenting capacity J Immunol 1999 163: 174–183

    CAS  PubMed  Google Scholar 

  35. Chen Y, Emtage P, Zhu Q et al. Induction of ErbB-2/neu-specific protective and therapeutic antitumor immunity using genetically modified dendritic cells: enhanced efficacy by cotransduction of gene encoding IL-12 Gene Ther 2001 8: 316–323

    Article  CAS  PubMed  Google Scholar 

  36. Kass E, Panicali D, Mazzara G et al. Granulocyte/macrophage-colony stimulating factor produced by recombinant avian poxviruses enriches the regional lymph nodes with antigen-presenting cells and acts as an immunoadjuvant Cancer Res 2001 61: 206–214

    CAS  PubMed  Google Scholar 

  37. Banchereau J, Steinman RM . Dendritic cells and the control of immunity Nature 1998 392: 245–252

    Article  CAS  PubMed  Google Scholar 

  38. Jonuleit H, Knop J, Enk AH . Cytokines and their effects on maturation, differentiation and migration of dendritic cells Arch Dermatol Res 1996 289: 1–8

    Article  CAS  PubMed  Google Scholar 

  39. Brunner C, Seiderer J, Schlamp A et al. Enhanced dendritic cell maturation by TNF-α or cytidine-phosphate-guanosine DNA drives T cell activation in vitro and therapeutic antitumor immune responses in vivo J Immunol 2000 165: 6278–6286

    Article  CAS  PubMed  Google Scholar 

  40. Cumberbatch M, Kimber I . Tumor necrosis factor-α is required for accumulation of dendritic cells in draining lymph nodes and for optimal contact sensitization Immunology 1995 84: 31–35

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kobayashi H, Wood M, Song Y et al. Defining promiscuous MHC class II helper T-cell epitopes for the HER-2/neu tumor antigen Cancer Res 2000 60: 5228–5236

    CAS  PubMed  Google Scholar 

  42. Ben-Levy R, Paterson H, Marshall C . A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway EMBO J 1994 13: 3302–3311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by a research grant (3-782) from Saskatchewan Cancer Agency.

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Authors and Affiliations

  1. Department of Oncology, Cancer Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Zhuang Chen, Hui Huang, Tim Chang, Svein Carlsen & Jim Xiang

  2. Department of Pathology, Cancer Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Anurag Saxena

  3. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    Robert Marr & Zhou Xing

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  1. Zhuang Chen
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Correspondence to Jim Xiang.

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Chen, Z., Huang, H., Chang, T. et al. Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor. Cancer Gene Ther 9, 778–786 (2002). https://doi.org/10.1038/sj.cgt.7700498

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