Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

CD8+ T cells, NK cells and IFN-γ are important for control of tumor with downregulated MHC class I expression by DNA vaccination

Gene Therapy volume 10, pages 1311–1320 (2003)Cite this article

Abstract

One of the major hurdles facing cancer immunotherapy is that cancers may downregulate expression of MHC class I molecules. The development of a suitable tumor model with downregulated MHC class I expression is critical for designing vaccines and immunotherapeutic strategies to control such tumors. We developed an E7-expressing murine tumor model with downregulated MHC class I expression, TC-1 P3 (A15). Using this model, we tested DNA and vaccinia vaccines for their ability to control tumors with downregulated MHC class I expression. We found that vaccination with DNA encoding E7 linked to Mycobacterial heat shock protein 70 (HSP70) generated a significant antitumor effect against TC-1 P3 (A15), while vaccination with E7/HSP70 vaccinia did not generate an appreciable antitumor effect. Lymphocyte depletion experiments revealed that both CD8+ T cells and NK cells were essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Furthermore, tumor protection experiments using IFN-γ knockout mice revealed that IFN-γ was essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Our results demonstrate that vaccination with E7/HSP70 DNA results in a significant antitumor effect against a neoplasm with downregulated MHC class I expression and the importance of CD8+ T cells, NK cells, and IFN-γ in generating this antitumor effect.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Chen CH, Wu TC . Experimental vaccine strategies for cancer immunotherapy. J Biomed Sci 1998; 5: 231.

    Article  CAS  PubMed  Google Scholar 

  2. Restifo NP et al. Identification of human cancers deficient in antigen processing. J Exp Med 1993; 177: 265.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrone S, Marincola FM . Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. Immunol Today 1995; 16: 487.

    Article  CAS  PubMed  Google Scholar 

  4. Korkolopoulou P et al. Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer. Br J Cancer 1996; 73: 148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sanda MG et al. Molecular characterization of defective antigen processing in human prostate cancer. J Natl Cancer Inst 1995; 87: 280.

    Article  CAS  PubMed  Google Scholar 

  6. Vitale M et al. HLA class I antigen and transporter associated with antigen processing (TAP1 and TAP2) down-regulation in high-grade primary breast carcinoma lesions. Cancer Res 1998; 58: 737.

    CAS  PubMed  Google Scholar 

  7. Vegh Z, Wang P, Vanky F, Klein E . Selectively down-regulated expression of major histocompatibility complex class I alleles in human solid tumors. Cancer Res 1993; 53: 2416.

    CAS  PubMed  Google Scholar 

  8. Koopman LA et al. Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer. J Exp Med 2000; 191: 961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sherritt M et al. Immunization with tumor-associated epitopes fused to an endoplasmic reticulum translocation signal sequence affords protection against tumors with down-regulated expression of MHC and peptide transporters. Int Immunol 2001; 13: 265.

    Article  CAS  PubMed  Google Scholar 

  10. Wu T-C et al. Engineering an intracellular pathway for MHC class II presentation of HPV-16 E7. Proc Natl Acad Sci 1995; 92: 11671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ji H et al. Targeting HPV-16 E7 to the endosomal/lysosomal compartment enhances the antitumor immunity of DNA vaccines against murine HPV-16 E7-expressing tumors. Hum Gene Ther 1999; 10: 2727.

    Article  CAS  PubMed  Google Scholar 

  12. Lin K-Y et al. Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 1996; 56: 21.

    CAS  PubMed  Google Scholar 

  13. Condon C et al. DNA-based immunization by in vivo transfection of dendritic cells. Nat Med 1996; 2: 1122.

    Article  CAS  PubMed  Google Scholar 

  14. Chen C-H et al. Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res 2000; 60: 1035.

    CAS  PubMed  Google Scholar 

  15. Hung CF et al. Enhancement of DNA vaccine potency by linkage of antigen gene to a gene encoding the extracellular domain of Fms-like tyrosine kinase 3-ligand. Cancer Res 2001; 61: 1080.

    CAS  PubMed  Google Scholar 

  16. Hung C-F et al. Cancer immunotherapy using a DNA vaccine encoding the translocation domain of a bacterial toxin linked to a tumor antigen. Cancer Res 2001; 61: 3698.

    CAS  PubMed  Google Scholar 

  17. Chen CH et al. Recombinant DNA vaccines protect against tumors that are resistant to recombinant vaccinia vaccines containing the same gene. Gene Ther 2001; 8: 128.

    Article  CAS  PubMed  Google Scholar 

  18. Zeh III HJ et al. High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy. J Immunol 1999; 162: 989.

    CAS  PubMed  Google Scholar 

  19. Dutoit V et al. Heterogeneous T-cell response to MAGE-A10(254–262): high avidity-specific cytolytic T lymphocytes show superior antitumor activity. Cancer Res 2001; 61: 5850.

    CAS  PubMed  Google Scholar 

  20. Savage PA, Boniface JJ, Davis MM . A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity 1999; 10: 485.

    Article  CAS  PubMed  Google Scholar 

  21. Weber JS, Rosenberg SA . Modulation of murine tumor major histocompatibility antigens by cytokines in vivo and in vitro. Cancer Res 1988; 48: 5818.

    CAS  PubMed  Google Scholar 

  22. Slifka MK, Whitton JL . Functional avidity maturation of CD8+ T cells without selection of higher affinity TCR. Nat Immunol 2001; 2: 711.

    Article  CAS  PubMed  Google Scholar 

  23. Margulies DH . TCR avidity: it's not how strong you make it, it's how you make it strong. Nat Immunol 2001; 2: 669.

    Article  CAS  PubMed  Google Scholar 

  24. Fahmy TM, Bieler JG, Edidin M, Schneck JP . Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen. Immunity 2001; 14: 135.

    CAS  PubMed  Google Scholar 

  25. Derby MA, Wang J, Margulies DH, Berzofsky JA . Two intermediate-avidity cytotoxic T lymphocyte clones with a disparity between functional avidity and MHC tetramer staining. Int Immunol 2001; 13: 817.

    Article  CAS  PubMed  Google Scholar 

  26. Alexander-Miller MA, Leggatt GR, Berzofsky JA . Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci USA 1996; 93: 4102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Derby M, Alexander-Miller M, Tse R, Berzofsky J . High-avidity CTL exploit two complementary mechanisms to provide better protection against viral infection than low-avidity CTL. J Immunol 2001; 166: 1690.

    Article  CAS  PubMed  Google Scholar 

  28. Seliger B, Maeurer MJ, Ferrone S . TAP off – tumors on. Immunol Today 1997; 18: 292.

    CAS  PubMed  Google Scholar 

  29. Porgador A, Mandelboim O, Restifo NP, Strominger JL . Natural killer cell lines kill autologous beta2-microglobulin-deficient melanoma cells: implications for cancer immunotherapy. Proc Natl Acad Sci USA 1997; 94: 13140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Multhoff G et al. Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells. Exp Hematol 1999; 27: 1627.

    Article  CAS  PubMed  Google Scholar 

  31. Dighe AS, Richards E, Old LJ, Schreiber RD . Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1994; 1: 447.

    Article  CAS  PubMed  Google Scholar 

  32. Kaplan DH et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 1998; 95: 7556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Seliger B, Pfizenmaier K . Post-transcriptional downregulation of MHC class I expression in oncogene-transformed cells is reverted by IFN-gamma and TNF-alpha. J Immunogenet 1989; 16: 315.

    Article  CAS  PubMed  Google Scholar 

  34. Klinman DM, Yamshchikov G, Ishigatsubo Y . Contribution of CpG motifs to the immunogenicity of DNA vaccines. J Immunol 1997; 158: 3635.

    CAS  PubMed  Google Scholar 

  35. Sparwasser T et al. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 1998; 28: 2045.

    Article  CAS  PubMed  Google Scholar 

  36. Jakob T et al. Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: a role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA. J Immunol 1998; 161: 3042.

    CAS  PubMed  Google Scholar 

  37. Ballas ZK, Rasmussen WL, Krieg AM . Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J Immunol 1996; 157: 1840.

    CAS  PubMed  Google Scholar 

  38. Alcami A, Smith GL . Vaccinia, cowpox, and camelpox viruses encode soluble gamma interferon receptors with novel broad species specificity. J Virol 1995; 69: 4633.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Alcami A, Smith GL . Soluble interferon-gamma receptors encoded by poxviruses. Comp Immunol Microbiol Infect Dis 1996; 19: 305.

    Article  CAS  PubMed  Google Scholar 

  40. Symons JA, Alcami A, Smith GL . Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity. Cell 1995; 81: 551.

    Article  CAS  PubMed  Google Scholar 

  41. Smith GL et al. Vaccinia virus immune evasion. Immunol Rev 1997; 159: 137.

    Article  CAS  PubMed  Google Scholar 

  42. Restifo NP et al. Molecular mechanisms used by tumors to escape immune recognition: immunogenetherapy and the cell biology of major histocompatibility complex class I. J Immunother 1993; 14: 182.

    Article  CAS  Google Scholar 

  43. Walter W et al. MHC class II antigen presentation pathway in murine tumours: tumour evasion from immunosurveillance? Br J Cancer 2000; 83: 1192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zheng P, Sarma S, Guo Y, Liu Y . Two mechanisms for tumor evasion of preexisting cytotoxic T-cell responses: lessons from recurrent tumors. Cancer Res 1999; 59: 3461.

    CAS  PubMed  Google Scholar 

  45. Seliger B, Maeurer MJ, Ferrone S . Antigen-processing machinery breakdown and tumor growth. Immunol Today 2000; 21: 455.

    Article  CAS  PubMed  Google Scholar 

  46. Johnsen AK, Templeton DJ, Sy M, Harding CV . Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. J Immunol 1999; 163: 4224.

    CAS  PubMed  Google Scholar 

  47. Hahne M et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 1996; 274: 1363.

    Article  CAS  PubMed  Google Scholar 

  48. Nagata S . Fas ligand and immune evasion. Nat Med 1996; 2: 1306.

    Article  CAS  PubMed  Google Scholar 

  49. Strand S et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells – a mechanism of immune evasion? Nat Med 1996; 2: 1361.

    Article  CAS  PubMed  Google Scholar 

  50. Edward M . Integrins and other adhesion molecules involved in melanocytic tumor progression. Curr Opin Oncol 1995; 7: 185.

    Article  CAS  PubMed  Google Scholar 

  51. Chouaib S et al. The host-tumor immune conflict: from immunosuppression to resistance and destruction. Immunol Today 1997; 18: 493.

    Article  CAS  PubMed  Google Scholar 

  52. Moss B, Earl P . Overview of the vaccinia virus expression system. Curr Prot Mol Biol, 2001; 3: 16.15.1.

  53. Earl P, Moss B . Preparation of cell cultures and vaccinia virus stocks. Curr Prot Mol Biol, 2001; 3: 16.16.1.

    Google Scholar 

  54. Earl P, Moss B . Generation of recombinant vaccinia viruses. Curr Prot Mol Biol, 2001; 3: 16.17.1.

    Google Scholar 

  55. Ji H et al. Antigen-specific immunotherapy for murine lung metastatic tumors expressing human papillomavirus type 16 E7 oncoprotein. Int J Cancer 1998; 78: 41.

    Article  CAS  PubMed  Google Scholar 

  56. Chen CH et al. Gene gun-mediated DNA vaccination induces antitumor immunity against human papillomavirus type 16 E7-expressing murine tumor metastases in the liver and lungs. Gene Ther 1999; 6: 1972.

    Article  CAS  PubMed  Google Scholar 

  57. Feltkamp MC et al. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur J Immunol 1993; 23: 2242.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs Robert Kurman, Drew Pardoll, and Hyam Levitsky for helpful discussions. We also thank Drs Richard Roden and Ralph Hruban for a critical review of the manuscript. We thank The Tetramer Core Facility at NIH for providing PE-labeled E7 (aa 49–57) peptide-H2-Db tetramer. Dr Wen-Fang Cheng (RE88P005) is a recipient of the NHRI physician scientist fellowship award. Dr Cheng is supported by National Science Committee of Taiwan (NSC91-2341-B-002-369) and National Taiwan University Hospital (NTUH 91-F002). Ken-Yu Lin is a Howard Hughes predoctoral fellow.

This work was supported by NIH 5 PO1 34582-01, U19 CA72108-02, RO1 CA72631-01, RO1 CA83706-01, PO1AI48203-01, and American Cancer Society.

Author information

Author notes

  1. W F Cheng and C F Hung: W-F Cheng and C-F Hung contributed equally to this paper

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    W F Cheng, C F Hung, K Y Lin, M Ling, J Juang, L He, C T Lin & T-C Wu

  2. Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan

    W F Cheng

  3. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan

    C T Lin

  4. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

  5. Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

  6. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

Authors
  1. W F Cheng
    View author publications

    Search author on:PubMed Google Scholar

  2. C F Hung
    View author publications

    Search author on:PubMed Google Scholar

  3. K Y Lin
    View author publications

    Search author on:PubMed Google Scholar

  4. M Ling
    View author publications

    Search author on:PubMed Google Scholar

  5. J Juang
    View author publications

    Search author on:PubMed Google Scholar

  6. L He
    View author publications

    Search author on:PubMed Google Scholar

  7. C T Lin
    View author publications

    Search author on:PubMed Google Scholar

  8. T-C Wu
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, W., Hung, C., Lin, K. et al. CD8+ T cells, NK cells and IFN-γ are important for control of tumor with downregulated MHC class I expression by DNA vaccination. Gene Ther 10, 1311–1320 (2003). https://doi.org/10.1038/sj.gt.3301982

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.gt.3301982

Keywords

This article is cited by

Search

Advanced search

Quick links