Immunologic Research

, Volume 32, Issue 1–3, pp 231–245 | Cite as

Interferon-γ and cancer immunoediting

  • Gavin P. Dunn
  • Hiroaki Ikeda
  • Allen T. Bruce
  • Catherine Koebel
  • Ravi Uppaluri
  • Jack Bui
  • Ruby Chan
  • Mark Diamond
  • J. Michael White
  • Kathleen C. F. Sheehan
  • Robert D. Schreiber
Article

Abstract

Over the last 12 yr, we have shown that interferony and lymphocytes collaborate to regulate tumor development in mice. Specifically, we found that the immune system not only prevents the growth of primary (carcinogen-induced and spontaneous) and transplanted tumors but also sculpts the immunogenicity of tumors that form. These observations led us to refine the old and controversial “cancer immuno-surveillance” hypothesis of Burnet and Thomas into one that we termed cancer immunoediting that better emphasizes the paradoxical host-protective and tumor-sculpting roles of immunity on developing tumors. Our current work focuses on defining the molecular mechanisms that underlie cancer immunoediting and exploring the implications of this process for cancer immunotherapy.

Key Words

Interferon-γ cancer Immunosurveillance signal transductio9n cancer immunoediting lymphocytes 

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References

  1. 1.
    Bach EA, Aguet M, Schreiber RD: The IFN-γ receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 1997;15:563–591.PubMedCrossRefGoogle Scholar
  2. 2.
    Schreiber GH, Schreiber RD: Interferon- γ; in The Cytokine Handbook, 4th ed. New York, Elsevier Science, 2003.Google Scholar
  3. 3.
    Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber RD: Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J Biol Chem 1996;271:27,954–27,961.CrossRefGoogle Scholar
  4. 4.
    Riley JK, Takeda K, Akira S, Schreiber RD. Interleukin-10 receptor signaling through the JAK-STAT pathway: requirement for two distinct receptor-derived signals for anti-inflammatory action. J Biol Chem 1999;274:16,513–16,521.CrossRefGoogle Scholar
  5. 5.
    Weaver BK, Bohn E, Gil MP, Judd BA, Sheehan KCF, Schreiber RD: TIGER (ABIN-3) is an IL-10 regulated inhibitor of NF-kB activation. 2004, submitted.Google Scholar
  6. 6.
    Ikeda H, Old LJ, Schreiber RD: The roles of IFN-γ in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 2002;13:95–109.PubMedCrossRefGoogle Scholar
  7. 7.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3:991–998.PubMedCrossRefGoogle Scholar
  8. 8.
    Dunn GP, Old LJ, Schreiber RD: The three Es of cancer immunoediting. Annu Rev Immunol 2004;22:329–360.PubMedCrossRefGoogle Scholar
  9. 9.
    Dunn GP, Old LJ, Schreiber RD: The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004;21:137–148.PubMedCrossRefGoogle Scholar
  10. 10.
    Dighe AS, Richards E, Old LJ, Schreiber RD: Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFNγ receptors. Immunity 1994;1:447–456.PubMedCrossRefGoogle Scholar
  11. 11.
    Dighe AS, Campbell D, Hsieh CS, Murphy KM, Schreiber RD: Tissue specific targeting of cytokine unresponsiveness in transgenic mice. Immunity 1995;3:657–666.PubMedCrossRefGoogle Scholar
  12. 12.
    Dighe AS, Farrar MA, Schreiber RD: Inhibition of cellular responsiveness to interferon-γ (IFNγ) induced by overexpression of inactive forms of the IFNγ receptor. J Biol Chem 1993;268:10,645–10,653.Google Scholar
  13. 13.
    Huang S, Hendriks W, Althage A, et al: Immune response in mice that lack the interferon-γ receptor. Science 1993;259:1742–1745.PubMedCrossRefGoogle Scholar
  14. 14.
    Meraz MA, White JM, Sheehan KCF, et al: Targeted disruption of the STAT1 gene in mice reveals unex pected physiologic specificity in the JAK-STAT signaling pathway. Cell 1996;84:431–442.PubMedCrossRefGoogle Scholar
  15. 15.
    Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD: Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 1998;95:7556–7561.PubMedCrossRefGoogle Scholar
  16. 16.
    Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD: IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001;410:1107–1111.PubMedCrossRefGoogle Scholar
  17. 17.
    Bruce AT, Dunn GP, Ikeda H, Schreiber RD: A molecular explanation for IFN-γ’s anti-tumor actions: increased tumor cell recognition and elimination by T cells. 2004, submitted.Google Scholar
  18. 18.
    Thomas L: Discussion; in Lawrence HS (ed): Cellular and Humoral Aspects of the Hypersensitive States. New York, Hoeber-Harper, 1959, pp 529–532.Google Scholar
  19. 19.
    Burnet FM: The concept of immunological surveillance. Prog Exp Tumor Res 1970;13:1–27.PubMedGoogle Scholar
  20. 20.
    Thomas L: On immunosurveillance in human cancer. Yale J Biol Med 1982;55:329–333.PubMedGoogle Scholar
  21. 21.
    Stutman O: Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science 1974;183:534–536.PubMedCrossRefGoogle Scholar
  22. 22.
    Hunig T: T-cell function and specificity in athymic mice. Immunol Today 1983;4:84–87.CrossRefGoogle Scholar
  23. 23.
    Maleckar JR, Sherman LA: The composition of the T cell receptor repertoire in nude mice. J Immunol 1987; 138:3873–3876.PubMedGoogle Scholar
  24. 24.
    Ikehara S, Pahwa RN, Fernandes G, Hansen CT, Good RA: Functional T cells in athymic nude mice. Proc Natl Acad Sci USA 1984;81:886–888.PubMedCrossRefGoogle Scholar
  25. 25.
    Herberman RB, Holden HT: Natural cell-mediated immunity. Adv Cancer Res 1978;27:305–377.PubMedGoogle Scholar
  26. 26.
    Heidelberger C: Chemical carcinogenesis. Annu Rev Biochem 1975;44:79–121.PubMedCrossRefGoogle Scholar
  27. 27.
    Kouri RE, Nebert DW: Genetic Regulation of susceptibility to polycyclic-hydrocarbon-induced tumors in the mouse; in Hiatt HH, Watson JD, Winsten JA (eds): Origins of Human Cancer, Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1977, pp 811–835.Google Scholar
  28. 28.
    Shinkai Y, Rathbun G, Lam KP, et al: RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 1992;68:855–867.PubMedCrossRefGoogle Scholar
  29. 29.
    Uppaluri R, Dunn GP, Old LJ, Schreiber RD: IFNγ receptor-STAT1 signaling and cancer immunoediting; in Seghal PB, Levy DD, Hirano T (eds): Signal Transducers and Activators of Transcription: Activation and Biology. New York, Kluwer Academic, 2003, pp 399–418.Google Scholar
  30. 30.
    Chan SR, Bruce AT, Cardiff RD, Schreiber RD: Characterization of mammary adenocarcinomas that develop spontaneously in aged STAT1-deficient mice. 2004, submitted.Google Scholar
  31. 31.
    Schreiber RD, Old LJ, Hayday AC, Smyth MJ: Response to ‘A cancer immunosurveillance controversy’. Nat Immunol 2004;5:4, 5.Google Scholar
  32. 32.
    Birkeland SA, Storm HH, Lamm LU, et al: Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer 1995;60:183–189.PubMedGoogle Scholar
  33. 33.
    Penn I. Sarcomas in organ allograft recipients. Transplantation 1995;60:1485–1491.PubMedCrossRefGoogle Scholar
  34. 34.
    Penn I: Malignant melanoma in organ allograft recipients. Transplantation 1996;61:274–278.PubMedCrossRefGoogle Scholar
  35. 35.
    Sheil AGR: Cancer in dialysis and transplant patients; in Morris PJ (ed): Kidney Transplantation, vol 5, Philadelphia, WB Saunders, 2001, pp 558–570.Google Scholar
  36. 36.
    MacKie RM, Reid R, Junor B: Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med 2003;348:567, 568.PubMedCrossRefGoogle Scholar
  37. 37.
    Elder GJ, Hersey P, Branley P: Remission of transplanted melanoma—clinical course and tumour cell characterisation. Clin Transplant 1997;11:565–568.PubMedGoogle Scholar
  38. 38.
    Suranyi MG, Hogan PG, Falk MC, et al: Advanced donor-origin melanoma in a renal transplant recipient: immunotherapy, cure, and retransplantation. Transplantation 1998;66:655–661.PubMedCrossRefGoogle Scholar
  39. 39.
    Clark WH Jr, Elder DE, Guerry DT, et al: Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 1989;81:1893–1904.PubMedCrossRefGoogle Scholar
  40. 40.
    Mihm MC Jr, Clemente CG, Cascinelli N: Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest 1996;74:43–47.PubMedGoogle Scholar
  41. 41.
    Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996;77:1303–1310.PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang L, Conejo-Garcia JR, Katsaros D, et al: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003;348:203–213.PubMedCrossRefGoogle Scholar
  43. 43.
    Naito Y, Saito K, Shiiba K, et al: CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998;58:3491–3494.PubMedGoogle Scholar
  44. 44.
    Schumacher K, Haensch W, Roefzaad C, Schlag PM: Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 2001;61:3932–3936.PubMedGoogle Scholar
  45. 45.
    Knuth A, Danowski B, Oettgen HF, Old LJ: T-cell-mediated cytotoxicity against autologous malignant melanoma: analysis with interleukin 2-dependent T-cell cultures. Proc Natl Acad Sci USA 1984;81:3511–3515.PubMedCrossRefGoogle Scholar
  46. 46.
    Darnell RB: Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain. Proc Natl Acad Sci USA 1996;93:4529–4536.PubMedCrossRefGoogle Scholar
  47. 47.
    Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB: Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 1998;4:1321–1324.PubMedCrossRefGoogle Scholar
  48. 48.
    Wheelock EF, Weinhold KJ, Levich J: The tumor dormant state. Adv Cancer Res 1981;34:107–140.PubMedCrossRefGoogle Scholar
  49. 49.
    Uhr JW, Tucker T, May RD, Siu H, Vitetta ES: Cancer dormancy: studies of the murine BCL 1 lymphoma. Cancer Res 1991;51:5045s-5053s.PubMedGoogle Scholar
  50. 50.
    Smyth MJ, Crowe NY, Godfrey DI: NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 2001;13:459–463.PubMedCrossRefGoogle Scholar
  51. 51.
    Girardi M, Oppenheim DE, Steele CR, et al: Regulation of cutaneous malignancy by gammadelta T cells. Science 2001;294:605–609.PubMedCrossRefGoogle Scholar
  52. 52.
    Street SE, Cretney E, Smyth MJ: Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis. Blood 2001;97:192–197.PubMedCrossRefGoogle Scholar
  53. 53.
    Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA: Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 2000;192:755–760.PubMedCrossRefGoogle Scholar
  54. 54.
    Street SE, Trapani JA, MacGregor D, Smyth MJ: Suppression of lymphoma and epithelial malignancies effected by interferon γ. J Exp Med 2002;196:129–134.PubMedCrossRefGoogle Scholar
  55. 55.
    Enzler T, Gillessen S, Manis JP, et al: Deficiencies of GM-CSF and interferon γ link inflammation and cancer. J Exp Med 2003;197:1213–1219.PubMedCrossRefGoogle Scholar
  56. 56.
    van den Broek MF, Kagi D, Ossendorp F, et al: Decreased tumor surveillance in perforin-deficient mice. J Exp Med 1996;184:1781–1790.PubMedCrossRefGoogle Scholar
  57. 57.
    Clarke K, Lee FT, Brechbiel MW, Smyth FE, Old LJ, Scott AM: Therapeutic efficacy of anti-Lewis(y) humanized 3S193 radioimmunotherapy in a breast cancer model: enhanced activity when combined with taxol chemotherapy. Clin Cancer Res 2000;6:3621–3628.PubMedGoogle Scholar
  58. 58.
    Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ: Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 2002;168:1356–1361.PubMedGoogle Scholar
  59. 59.
    Takeda K, Smyth MJ, Cretney E, et al: Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 2002;195:161–169.PubMedCrossRefGoogle Scholar
  60. 60.
    Smyth MJ, Thia KY, Street SE, et al: Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 2000;191:661–668PubMedCrossRefGoogle Scholar
  61. 61.
    Noguchi Y, Jungbluth A, Richards E, Old LJ: Effect of interleukin 12 on tumor induction by 3-methylcholanthrene. Proc Natl Acad Sci USA 1996;93:11,798–11,801.CrossRefGoogle Scholar
  62. 62.
    Hayakawa Y, Rovero S, Forni G, Smyth MJ: Alphagalactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. Proc Natl Acad Sci USA 2003;100:9464–9469.PubMedCrossRefGoogle Scholar
  63. 63.
    Hayashi T, Faustman DL: Development of spontaneous uterine tumors in low molecular mass polypeptide-2 knockout mice. Cancer Res 2002;62:24–27.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Gavin P. Dunn
    • 1
  • Hiroaki Ikeda
    • 1
  • Allen T. Bruce
    • 1
  • Catherine Koebel
    • 1
  • Ravi Uppaluri
    • 1
  • Jack Bui
    • 1
  • Ruby Chan
    • 1
  • Mark Diamond
    • 1
  • J. Michael White
    • 1
  • Kathleen C. F. Sheehan
    • 1
  • Robert D. Schreiber
    • 1
  1. 1.Department of Pathology and Immunology, Center for ImmunologyWashington University School of MedicineSt. Louis

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