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.

  • Acquired Diseases
  • Published:

Gene transfer of human interferon gamma complementary DNA into a renal cell carcinoma line enhances MHC-restricted cytotoxic T lymphocyte recognition but suppresses non-MHC-restricted effector cell activity

Gene Therapy volume 7, pages 950–959 (2000)Cite this article

Abstract

Even though renal cell carcinomas (RCC) are thought to be immunogenic, many tumors express variations in surface molecules and intracellular proteins that hinder induction of optimal antitumor responses. Interferon gamma (IFNγ) stimulation can correct some of these deficiencies. Therefore, we introduced the complementary DNA (cDNA) encoding human IFNγ into a well-characterized RCC line that has been selected for development of an allogeneic tumor cell vaccine for treatment of patients with metastatic disease. Studies were performed to determine how endogenous IFNγ expression influences tumor cell immunogenicity. IFNγ transductants showed minimal increases in surface expression of MHC class I and adhesion molecules but expression of class II molecules was induced. Proteins of the transporter associated with antigen processing (TAP) and low molecular weight polypeptide (LMP) were constitutively expressed at high levels. The transductants stimulated allospecific cytotoxic T lymphocytes (CTL); however, they were not better than unmodified tumor cells in this capacity. Endogenous IFNγ expression enhanced tumor cell recognition by MHC-restricted, tumor antigen-specific CTL but suppressed recognition by non-MHC-restricted cytotoxic cells. Thus, the functional consequences of IFNγ expression varied with respect to the type of effector cell and were not always beneficial for tumor cell recognition.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Ostrand-Rosenberg S . Tumor immunotherapy: the tumor cell as an antigen-presenting cell Curr Opin Immunol 1994 6: 722–727

    Article  CAS  PubMed  Google Scholar 

  2. Hellström KE, Hellström I, Chien L . Can co-stimulated tumor immunity be therapeutically efficacious? Immunol Rev 1995 145: 123–145

    Article  PubMed  Google Scholar 

  3. Blankenstein T, Rowley DA, Schreiber H . Cytokines and cancer: experimental systems Curr Opin Immunol 1991 3: 694–698

    Article  CAS  PubMed  Google Scholar 

  4. Oettgen HF . Cytokines in clinical cancer therapy Curr Opin Immunol 1991 3: 699–705

    Article  CAS  PubMed  Google Scholar 

  5. Pardoll D . Immunotherapy with cytokine gene-transduced tumor cells: the next wave in gene therapy for cancer Curr Opin Oncol 1992 4: 1124–1129

    Article  CAS  PubMed  Google Scholar 

  6. Motzer RJ, Bander NH, Nanus DM . Renal-cell carcinoma New Engl J Med 1996 335: 865–875

    Article  CAS  PubMed  Google Scholar 

  7. Schendel DJ et al. Cellular and molecular analyses of MHC-restricted and non-MHC-restricted effector cells recognizing renal cell carcinomas: problems and perspectives for immunotherapy J Mol Med 1997 75: 400–413

    Article  CAS  PubMed  Google Scholar 

  8. Mule JJ, Shu S, Schwarz SL, Rosenberg SA . Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2 Science 1984 225: 1487–1489

    Article  CAS  PubMed  Google Scholar 

  9. Ortaldo JR, Mason A, Overton R . Lymphokine-activated killer cells. Analysis of progenitors and effectors J Exp Med 1986 164: 1193–1205

    Article  CAS  PubMed  Google Scholar 

  10. Phillips JH, Lanier LL . Dissection of the lymphokine-activated killer phenomenon. Relative contribution of peripheral blood natural killer cells and T lymphocytes to cytolysis J Exp Med 1986 164: 814–825

    Article  CAS  PubMed  Google Scholar 

  11. Mingari MC et al. Phenotypic and functional analysis of human CD3+ and CD3− clones with ‘lymphokine-activated killer’ (LAK) activity. Frequent occurrence of CD3+ LAK clones which produce interleukin-2 Int J Cancer 1987 40: 495–498

    Article  CAS  PubMed  Google Scholar 

  12. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA . Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes J Exp Med 1982 155: 1823–1841

    Article  CAS  PubMed  Google Scholar 

  13. Rosenberg S . Lymphokine-activated killer cells: a new approach to immunotherapy of cancer J Natl Cancer Inst 1985 75: 595–603

    CAS  PubMed  Google Scholar 

  14. O'Shea J, Ortaldo JR . The biology of natural killer cell: insights into the molecular basis of function. In: Lewis CE, McGee JO (eds) The Natural Killer Cell Oxford University Press: New York 1992 pp 2–40

    Google Scholar 

  15. Zarcone D et al. Antibodies to adhesion molecules inhibit the lytic function of MHC-unrestricted cytotoxic cells by preventing their activation Cell Immunol 1992 143: 389–404

    Article  CAS  PubMed  Google Scholar 

  16. Trinchieri G . Recognition of major histocompatibility complex class I antigens by natural killer cells J Exp Med 1994 180: 417–421

    Article  CAS  PubMed  Google Scholar 

  17. Belldegrun A et al. Human tumor infiltrating lymphocytes. Analysis of lymphokine mRNA expression and relevance to cancer immunotherapy J Immunol 1989 142: 4520–4526

    CAS  PubMed  Google Scholar 

  18. Finke JH et al. Characterization of the cytolytic activity of CD4+ and CD8+ tumor-infiltrating lymphocytes in human renal cell carcinoma Cancer Res 1990 50: 2363–2370

    CAS  PubMed  Google Scholar 

  19. Koo AS et al. Autologous tumor-specific cytotoxicity of tumor-infiltrating lymphocytes derived from human renal cell carcinoma J Immunother 1991 10: 347–354

    Article  CAS  PubMed  Google Scholar 

  20. Finke JH et al. Characterization of a human renal cell carcinoma specific cytotoxic CD8+ T cell line J Immunother 1992 11: 1–11

    Article  CAS  PubMed  Google Scholar 

  21. Schendel DJ et al. Tumor-specific lysis of human renal cell carcinomas by tumor-infiltrating lymphocytes. I. HLA-A2-restricted recognition of autologous and allogeneic tumor lines J Immunol 1993 151: 4209–4220

    CAS  PubMed  Google Scholar 

  22. Bernhard H et al. Tumor associated antigens in human renal cell carcinoma: MHC-restricted recognition by cytotoxic T lymphocytes Tissue Antigens 1996 48: 22–31

    Article  CAS  PubMed  Google Scholar 

  23. Bernhard H et al. Recognition of human renal cell carcinoma and melanoma by HLA-A2- restricted cytotoxic T lymphocytes is mediated by shared peptide epitopes and up-regulated by interferon-gamma Scand J Immunol 1996 44: 285–292

    Article  CAS  PubMed  Google Scholar 

  24. Brouwnenstijn N et al. Renal-cell carcinoma-specific lysis by cytotoxic T-lymphocyte clones isolated from peripheral blood lymphocytes and tumor-infiltrating lymphocytes Int J Cancer 1996 68: 177–182

    Article  Google Scholar 

  25. Boon T, Coulie PG, Van den Eynde B . Tumor antigens recognized by T cells Immunol Today 1997 18: 267–268

    Article  CAS  PubMed  Google Scholar 

  26. Gaugler B et al. A new gene coding for an antigen recognized by autologous cytolytic T lymphocytes on a human renal carcinoma Immunogenetics 1996 44: 323–330

    Article  CAS  PubMed  Google Scholar 

  27. Basham TY, Merigan TC . Recombinant interferon-g increases HLA-DR synthesis and expression J Immunol 1983 130: 1492–1494

    CAS  PubMed  Google Scholar 

  28. Schwartz R et al. Induction of HLA class-II antigen expression on human carcinoma cell lines by IFN-Gamma Int J Cancer 1985 35: 245–250

    Article  CAS  PubMed  Google Scholar 

  29. el Asrar AM et al. Recombinant interferon-gamma induces HLA-DR expression on human corneal epithelial and endothelial cells in vitro: a preliminary report Br J Ophthalmol 1989 73: 587–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zarcone D et al. Antibodies to adhesion molecules inhibit the lytic function of MHC-unrestricted cytotoxic cells by preventing their activation Cell Immunol 1992 143: 389–404

    Article  CAS  PubMed  Google Scholar 

  31. Boehm U, Klamp T, Groot M, Howard JC . Cellular responses to interferon-gamma Annu Rev Immunol 1997 15: 749–795

    Article  CAS  PubMed  Google Scholar 

  32. Uebel S, Tampe R . Specificity of the proteasome and the TAP transporter Curr Opin Immunol 1999 11: 203–208

    Article  CAS  PubMed  Google Scholar 

  33. Spies T, DeMars R . Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter Nature 1991 351: 323–324

    Article  CAS  PubMed  Google Scholar 

  34. Monaco JJ . Genes in the MHC that may affect antigen processing Curr Opin Immunol 1992 4: 70–73

    Article  CAS  PubMed  Google Scholar 

  35. Ogasawara M, Rosenberg SA . Enhanced expression of HLA molecules and stimulation of autologous human tumor infiltrating lymphocytes following transduction of melanoma cells with gamma-interferon genes Cancer Res 1993 53: 3561–3568

    CAS  PubMed  Google Scholar 

  36. Abdel Wahab ZA et al. Transduction of human melanoma cells with the gamma interferon gene enhances cellular immunity Cancer Gene Ther 1994 1: 171–179

    CAS  PubMed  Google Scholar 

  37. Zier KS, Gansbacher B . Tumour cell vaccines that secrete interleukin-2 (IL-2) and interferongamma (IFNgamma) are recognised by T cells while resisting destruction by natural killer (NK) cells Eur J Cancer 1996 32A: 1408–1412

    Article  CAS  PubMed  Google Scholar 

  38. Pende D et al. The susceptibility to natural killer cell-mediated lysis of HLA class I-positive melanomas reflects the expression of insufficient amounts of different HLA class I alleles Eur J Immunol 1998 28: 2384–2394

    Article  CAS  PubMed  Google Scholar 

  39. Taniguchi K et al. Interferon gamma induces lung colonization by intravenously inoculated B16 melanoma cells in parallel with enhanced expression of class I major histocompatibility complex antigens Proc Natl Acad Sci USA 1987 84: 3405–3409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lollini P-L et al. Inhibition of tumor growth and enhancement of metastasis after transfection of the gamma-interferon gene Int J Cancer 1993 55: 320–329

    Article  CAS  PubMed  Google Scholar 

  41. Jantzer P, Schendel DJ . Human renal cell carcinoma antigen-specific cytotoxic T lymphocytes: antigen-driven selection and long-term persistence in vivo Cancer Res 1998 58: 3078–3086

    CAS  PubMed  Google Scholar 

  42. Schendel DJ, Gansbacher B . Tumor-specific lysis of human renal cell carcinomas by tumor-infiltrating lymphocytes: modulation of recognition through retroviral transduction of tumor cells with interleukin 2 complementary DNA and exogenous alpha interferon treatment Cancer Res 1993 53: 4020–4025

    CAS  PubMed  Google Scholar 

  43. Gastl G et al. Retroviral vector-mediated lymphokine gene transfer into human renal cancer cells Cancer Res 1992 52: 1–8

    Google Scholar 

  44. Restifo NR et al. Identification of human cancers deficient in antigen processing J Exp Med 1993 177: 265–272

    Article  CAS  PubMed  Google Scholar 

  45. Seliger B et al. Analysis of the major histocompatibility complex class I antigen presentation machinery in normal and malignant renal cells: evidence for deficiencies associated with transformation and progression Cancer Res 1996 56: 1756–1760

    CAS  PubMed  Google Scholar 

  46. Quesada JR, Kurzrock R, Sherwin SA, Gutterman JU . Phase II studies of recombinant human interferon gamma in metastatic renal cell carcinoma J Biol Response Mod 1987 6: 20–27

    CAS  PubMed  Google Scholar 

  47. Meyskens FL Jr et al. Recombinant human interferon gamma: adverse effects in high-risk stage I and II cutaneous malignant melanoma (letter) J Natl Cancer Inst 1990 82: 1071–1071

    Article  PubMed  Google Scholar 

  48. Allhoff EP et al. Current clinical relevance of immunotherapy in metastatic renal cell cancer World J Urol 1991 9: 228–231

    Article  Google Scholar 

  49. Aulitzky W et al. Successful treatment of metastatic renal cell carcinoma with a biologically active dose of recombinant interferon-gamma J Clin Oncol 1989 7: 1875–1884

    Article  CAS  PubMed  Google Scholar 

  50. Otto F, Mackensen A, Mertelsmann R, Engelhardt R . Complete response of metastatic renal cell carcinoma to low-dose interferon-gamma treatment Cancer Immunol Immunother 1995 40: 115–118

    Article  CAS  PubMed  Google Scholar 

  51. Otto U, Schneider AW, Conrad S, Klosterhalfen H . Recombinant alpha-2 or gamma interferon in the treatment of metastatic renal cell carcinoma: results of two phase II/III trials Prog Clin Biol Res 1990 350: 275–282

    CAS  PubMed  Google Scholar 

  52. Rosenberg SA . Karnofsky Memorial Lecture. The immunotherapy and gene therapy of cancer J Clin Oncol 1992 10: 180–199

    Article  CAS  PubMed  Google Scholar 

  53. Blankenstein T . Increasing tumour immunogenicity by genetic modification Eur J Cancer 1994 30A: 1182–1187

    Article  CAS  PubMed  Google Scholar 

  54. Pardoll DM, Topalian SL . The role of CD4+ T cell responses in antitumor immunity Curr Opin Immunol 1998 10: 588–594

    Article  CAS  PubMed  Google Scholar 

  55. Pardoll DM . Paracrine cytokine adjuvants in cancer immunotherapy Annu Rev Immunol 1995 13: 399–415

    Article  CAS  PubMed  Google Scholar 

  56. Itoh K, Tilden AB, Balch CM . Lysis of human solid tumor cells by lymphokine-activated natural killer cells J Immunol 1986 136: 3910–3915

    CAS  PubMed  Google Scholar 

  57. Stotter H et al. Cytokines alter target cell susceptibility to lysis. II. Evaluation of tumor infiltrating lymphocytes J Immunol 1989 142: 1767–1773

    CAS  PubMed  Google Scholar 

  58. Shieh DC, Kao KJ . Proportional amplification of individual HLA-A and -B antigens during upregulated expression of total class I HLA molecules Hum Immunol 1995 42: 174–180

    Article  CAS  PubMed  Google Scholar 

  59. Panelli MC et al. Interferon gamma (IFNgamma) gene transfer of an EMT6 tumor that is poorly responsive to IFNgamma stimulation: increase in tumor immunogenicity is accompanied by induction of a mouse class II transactivator and class II MHC Cancer Immunol Immunother 1996 42: 99–107

    Article  CAS  PubMed  Google Scholar 

  60. Browder TM, Dunbar CE, Nienhuis AW . Private and public autocrine loops in neoplastic cells Cancer Cells 1989 1: 9–17

    CAS  PubMed  Google Scholar 

  61. Porgador A et al. Antimetastatic vaccination of tumor-bearing mice with two types of IFN-gamma gene-inserted tumor cells J Immunol 1993 150: 1458–1470

    CAS  PubMed  Google Scholar 

  62. Yin D et al. Interferon-gamma induces a decrease in the susceptibility of human glioma cells to lysis by lymphokine-activated killer cells Neurosurgery 1994 35: 113–118

    Article  CAS  PubMed  Google Scholar 

  63. Takahashi C et al. Cytokine modulation of interactions between cultured human renal tubular and lymphoid blast cells Pathol Res Pract 1995 191: 1–7

    Article  CAS  PubMed  Google Scholar 

  64. Schendel DJ, Wank R . Production of human T cell growth factor Hum Immunol 1981 2: 325–332

    Article  CAS  PubMed  Google Scholar 

  65. Gansbacher B et al. Retroviral gene transfer induced constitutive expression of interleukin-2 or interferon-gamma in irradiated human melanoma cells Blood 1992 80: 2817–2825

    CAS  PubMed  Google Scholar 

  66. Schendel DJ, Wank R, Dupont B . Standardization of the human in vitro cell-mediated lympholysis technique Tissue Antigens 1979 13: 112–120

    Article  CAS  PubMed  Google Scholar 

  67. Lämmli UK . Cleavage of structural proteins during the assembly of the head of bacteriophage T4 Nature 1970 227: 680–685

    Article  Google Scholar 

  68. Meyer TH et al. Functional expression and purification of the ABC transporter complex associated with antigen processing (TAP) in insect cells FEBS Lett 1994 351: 443–447

    Article  CAS  PubMed  Google Scholar 

  69. Van Endert PM et al. A sequential model for peptide binding and transport by the transporters associated with antigen processing Immunity 1994 1: 491–500

    Article  CAS  PubMed  Google Scholar 

  70. Ehring B et al. Effects of major histocompatibility complex encoded subunits on the peptidase and proteolytic activities of human 20s proteasomes: cleavage of proteins and antigenic peptides Eur J Biochem 1996 235: 404–415

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank R Oberneder and A Hofstetter for their sustained clinical support, M Morawietz and H Stepp for help with graphics and J Johnson and D Novick for providing relevant mAbs. This work was supported by grants of the Deutsche Forschungsgemeinschaft (SFB455 B10 and Ho1596/3-2).

Author information

Author notes

  1. S Urlinger

    Present address: Institute for Microbiology, Friedrich-Alexander-University Erlangen-Nürnberg, Germany

Authors and Affiliations

  1. Institute of Molecular Immunology, GSF National Research Center for the Environment and Health, Munich, Germany

    DJ Schendel, CS Falk, E Nößner, B Maget & S Kressenstein

  2. Institute of Physiological Chemistry, Philipps-University Marburg, Munich, Germany

    S Urlinger & R Tampé

  3. Institute for Experimental Oncology and Therapy Research, Technical University, Munich, Germany

    B Gansbacher

Authors
  1. DJ Schendel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. CS Falk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Nößner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Maget
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Kressenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Urlinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Tampé
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Gansbacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schendel, D., Falk, C., Nößner, E. et al. Gene transfer of human interferon gamma complementary DNA into a renal cell carcinoma line enhances MHC-restricted cytotoxic T lymphocyte recognition but suppresses non-MHC-restricted effector cell activity. Gene Ther 7, 950–959 (2000). https://doi.org/10.1038/sj.gt.3301187

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301187

Keywords

This article is cited by

Search

Advanced search

Quick links