Cancer Immunology, Immunotherapy

, Volume 53, Issue 2, pp 86–91

Signal transducer and activator of transcription 6 (Stat6) and CD1: inhibitors of immunosurveillance against primary tumors and metastatic disease

  • Suzanne Ostrand-Rosenberg
  • Pratima Sinha
  • Virginia Clements
  • Samudra I. Dissanayake
  • Seth Miller
  • Cordula Davis
  • Erika Danna
Symposium in Writing


Many tumor immunologists favor the hypothesis that optimal anti-tumor activity is mediated by type 1 CD4+ and CD8+ T cells, and that the production of type 2 CD4+ T cells may be counterproductive for effective anti-tumor immunity. Since Stat6-deficient or “knockout” mice lack the signal transducer and activator of transcription-6 protein and are unable to transmit signals initiated by the type 2 cytokines, IL-4 and IL-13, they have been studied to confirm the Th1 vs Th2 paradigm. Using transplantable tumor cells that cause primary solid tumors and metastatic disease, as well as a spontaneous transgenic tumor model, multiple studies have demonstrated that Stat6-/- mice are able to reject or delay primary tumor growth, prevent recurrence of primary tumors, and/or reject established, spontaneous metastatic disease. Deletion of the Stat6 gene, therefore, provides significantly enhanced immunosurveillance. Comparable experiments with CD1-deficient mice, which lack NKT cells and hence are deficient for IL-13, give similar results and suggest that removal of NKT cells also enhances immunosurveillance. Because immunity is enhanced in the absence of Stat6 or CD1, it has been hypothesized that these deletions result in the removal of an inhibitor that blocks constitutive immunosurveillance. Several mechanisms have been tested as potential inhibitors, including CD4+CD25+ T regulatory cells, IL-13, a Th2 shift, and myeloid suppressor cells. Although the first three mechanisms do not appear to be relevant, regression of myeloid suppressor cells in Stat6-deficient and CD1-deficient mice may be responsible for enhanced immunosurveillance. Although additional studies are clearly needed to clarify the mechanism(s) underlying improved anti-tumor immunity in Stat6-/- and CD1-/- mice, deletion of these genes results in a potent anti-tumor immunity and may be a basis for an immunotherapy strategy.



signal transducer and activator of transcription 6


myeloid suppressor cell


transgenic mice that spontaneously develop mammary carcinoma


Stat6-deficient, BALB/c NeuT mice


Stat6-deficient, interferon-γ-deficient BALB/c mice


  1. 1.
    Aslakson C, Miller F (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52:1399PubMedGoogle Scholar
  2. 2.
    Bellone G, Turletti A, Artusio E, Mareschi K, Carbone A, Tibaudi D, Robecchi A, Emanuelli G, Rodeck U (1999) Tumor-associated transforming growth factor-beta and interleukin-10 contribute to a systemic Th2 immune phenotype in pancreatic carcinoma patients. Am J Pathol 155:537PubMedGoogle Scholar
  3. 3.
    Boggio K, Nicoletti G, Di Carlo E, Cavallo F, Landuzzi L, Melani C, Giovarelli M, Rossi I, Nanni P, De Giovanni C, Bouchard P, Wolf S, Modesti A, Musiani P, Lollini PL, Colombo MP, Forni G (1998) Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J Exp Med 188:589PubMedGoogle Scholar
  4. 4.
    Bronte V, Serafini P, Apolloni E, Zanovello P (2001) Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J Immunother 24:431CrossRefPubMedGoogle Scholar
  5. 5.
    Constant S, Bottomly K (1997) Induction of the TH1 and TH2 CD4+ T cell responses: alternative approaches. Annu Rev Immunol 15:297PubMedGoogle Scholar
  6. 6.
    Dobrzanski MJ, Reome JB, Dutton RW (1999) Therapeutic effects of tumor-reactive type 1 and type 2 CD8+ T cell subpopulations in established pulmonary metastases. J Immunol 162:6671PubMedGoogle Scholar
  7. 7.
    Dobrzanski MJ, Reome JB, Dutton RW (2001) Role of effector cell-derived IL-4, IL-5, and perforin in early and late stages of type 2 CD8 effector cell-mediated tumor rejection. J Immunol 167:424PubMedGoogle Scholar
  8. 8.
    Gajewski TF, Fallarino F, Uyttenhove C, Boon T (1996) Tumor rejection requires a CTLA4 ligand provided by the host or expressed on the tumor: superiority of B7–1 over B7–2 for active tumor immunization. J Immunol 156:2909PubMedGoogle Scholar
  9. 9.
    Heim M (1999) The Jak-STAT pathway: cytokine signalling from the receptor to the nucleus. J Recept Signal Transduct Res 19:75PubMedGoogle Scholar
  10. 10.
    Hu HM, Urba WJ, Fox BA (1998) Gene-modified tumor vaccine with therapeutic potential shifts tumor-specific T cell response from a type 2 to a type 1 cytokine profile. J Immunol 161:3033PubMedGoogle Scholar
  11. 11.
    Ihle J, Nosaka T, Thierfelder W, Quelle F, Shimoda K (1997) Jaks and Stats in cytokine signaling. Stem Cells [Supp 1]:105Google Scholar
  12. 12.
    Jensen SM, Meijer SL, Kurt RA, Urba WJ, Hu HM, Fox BA (2003) Regression of a mammary adenocarcinoma in STAT6-/- mice is dependent on the presence of STAT6-reactive T cells. J Immunol 170:2014PubMedGoogle Scholar
  13. 13.
    Joyce S, Van Kaer L (2003) CD1-restricted antigen presentation: an oily matter. Curr Opin Immunol 15:95PubMedGoogle Scholar
  14. 14.
    Kacha AK, Fallarino F, Markiewicz MA, Gajewski TF (2000) Cutting edge: spontaneous rejection of poorly immunogenic P1.HTR tumors by Stat6-deficient mice. J Immunol 165:6024PubMedGoogle Scholar
  15. 15.
    Kaplan M, Grusby M (1998) Regulation of T helper cell differentiation by STAT molecules. J Leukoc Biol 64:2PubMedGoogle Scholar
  16. 16.
    Kobayashi M, Kobayashi H, Pollard RB, Suzuki F (1998) A pathogenic role of Th2 cells and their cytokine products on the pulmonary metastasis of murine B16 melanoma. J Immunol 160:5869PubMedGoogle Scholar
  17. 17.
    Liu K, Gaffen S, Goldsmith M (1998) JAK/STAT signaling by cytokine receptors. Curr Opin Immunol 10:271PubMedGoogle Scholar
  18. 18.
    Lucchini F, Sacco MG, Hu N, Villa A, Brown J, Cesano L, Mangiarini L, Rindi G, Kindl S, Sessa F et al (1992) Early and multifocal tumors in breast, salivary, harderian and epididymal tissues developed in MMTY-Neu transgenic mice. Cancer Lett 64:203PubMedGoogle Scholar
  19. 19.
    Matsui S, Ahlers JD, Vortmeyer AO, Terabe M, Tsukui T, Carbone DP, Liotta LA, Berzofsky JA (1999) A model for CD8+ CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL. J Immunol 163:184PubMedGoogle Scholar
  20. 20.
    Mattes J, Hulett M, Xie W, Hogan S, Rothenberg ME, Foster P, Parish C (2003) Immunotherapy of cytotoxic T cell-resistant tumors by T helper 2 cells: an eotaxin and STAT6-dependent process. J Exp Med 197:387PubMedGoogle Scholar
  21. 21.
    Miller F, Miller B, Heppner G (1983) Characterization of metastatic heterogeneity among subpopulations of a single mouse mammary tumor: heterogeneity in phenotypic stability. Invasion Metastasis 3:22PubMedGoogle Scholar
  22. 22.
    Murata T, Obiri NI, Puri RK (1998) Structure of and signal transduction through interleukin-4 and interleukin-13 receptors (review). Int J Mol Med 1:551PubMedGoogle Scholar
  23. 23.
    North RJ, Digiacom A, Dye E (1987) Suppression of antitumor immunity. In: Den Otter W, Ruitenberg EJ (eds) Tumor immunology: mechanisms, diagnosis, therapy. Elsevier, Amsterdam, p 125Google Scholar
  24. 24.
    Ostrand-Rosenberg S, Grusby MJ, Clements VK (2000) Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol 165:6015PubMedGoogle Scholar
  25. 25.
    Ostrand-Rosenberg S, Clements VK, Terabe M, Park JM, Berzofsky JA, Dissanayake SK (2002) Resistance to metastatic disease in STAT6-deficient mice requires hemopoietic and nonhemopoietic cells and is IFN-gamma dependent. J Immunol 169:5796PubMedGoogle Scholar
  26. 26.
    Piccirillo CA, Shevach EM (2001) Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J Immunol 167:1137PubMedGoogle Scholar
  27. 27.
    Pulaski B, Ostrand-Rosenberg S (1998) MHC class II and B7.1 immunotherapeutic cell-based vaccine reduces spontaneous mammary carcinoma metastases without affecting primary tumor growth. Cancer Res 58:1486PubMedGoogle Scholar
  28. 28.
    Pulaski B, Ostrand-Rosenberg S (2000) Mouse 4T1 breast tumor model. In: Coligan JE, Kruisbeek AM, Margulies DH, Shevach EM, Strober W (eds) Current protocols in immunology. Wiley, New York, p 20.2.1Google Scholar
  29. 29.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151PubMedGoogle Scholar
  30. 30.
    Salvadori S, Martinelli G, Zier K (2000) Resection of solid tumors reverses T cell defects and restores protective immunity. J Immunol 164:2214PubMedGoogle Scholar
  31. 31.
    Serafini P, De Santo C, Marigo I, Cingarlini S, Dolcetti L, Gallina G, Zanovello P, Bronte V (2003) Derangement of immune responses by myeloid suppressor cells. Cancer Immunol Immunother (in press)Google Scholar
  32. 32.
    Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389PubMedGoogle Scholar
  33. 33.
    Shimoda K, van Deursen J, Sangster M, Sarawar S, Carson R, Tripp R, Chu C, Quelle F, Nosaka T, Vagnali D, Doherty P, Grosveld G, Paul W, Ihle J (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with distrupted STAT6 gene. Nature 380:630PubMedGoogle Scholar
  34. 34.
    Shurin M, Lu L, Kalinski P, Stewart-Akers A, Lotze M (1999) Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin Immunopathol 21:339PubMedGoogle Scholar
  35. 35.
    Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823PubMedGoogle Scholar
  36. 36.
    Terabe M, Matsui S, Noben-Trauth N, Chen H, Watson C, Donaldson DD, Carbone DP, Paul WE, Berzofsky JA (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1:515PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Suzanne Ostrand-Rosenberg
    • 1
  • Pratima Sinha
    • 1
  • Virginia Clements
    • 1
  • Samudra I. Dissanayake
    • 1
  • Seth Miller
    • 1
  • Cordula Davis
    • 1
  • Erika Danna
    • 1
  1. 1.Department of Biological SciencesUniversity of Maryland, Baltimore CountyBaltimoreUSA

Personalised recommendations