Escape of Tumors From the Immune System

Role of the Transforming Growth Factor-ß-Signaling Pathway
  • Gerard C. Blobe
Part of the Cancer Drug Discovery and Development book series (CDD&D)


It is widely accepted that tumors may evade the immune response by a number of different mechanisms described in Chapter 6 including: antigenic variation, downregulation of tumor-specific antigens, downregulation of major histocompatibility complex (MHC) molecules, and lack of sufficient costimulation to T cells by tumors that are considered as “self.” Mechanisms by which tumors may suppress the immune system include: interference with antigen processing and/or presentation, induction of apoptosis in lymphocytes by Fas ligand (FasL) or other “death” receptors, interference with the ability of leukocytes to migrate into the tumor, and active tumor-mediated immunosuppression. Although support for all of these mechanisms exists in experimental models and/or specific tumor types, there is mounting evidence that active tumor-mediated immunosuppression may be the most general and potent way for human tumors to escape the immune system. In addition, current evidence supports a model by which this active tumor-mediated immunosuppression is largely the result of secretion of the potent immunosuppressive cytokine, transforming growth factor-ß (TGF-ß). In this review, the evidence supporting such a role for TGF-ß and the mechanisms by which TGF-ß may be acting to suppress the immune system are discussed. Finally, strategies to target the TGFß-signaling pathway to ultimately improve the success of immunotherapy for human cancers are explored.


Cell Growth Differ Transform Growth Factor Beta Receptor TGFbeta Signaling Soluble Extracellular Domain Local Tumor Environment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67:753–791.PubMedCrossRefGoogle Scholar
  2. 2.
    Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett 2002; 82:85–91.PubMedCrossRefGoogle Scholar
  3. 3.
    Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dey 2002; 12:22–29.CrossRefGoogle Scholar
  4. 4.
    Kulkarni AB, Thyagarajan T, Letterio JJ. Function of cytokines within the TGF-beta superfamily as determined from transgenic and gene knockout studies in mice. Curr Mol Med 2002; 2:303–327.PubMedCrossRefGoogle Scholar
  5. 5.
    Crawford SE, Stellmach V, Murphy-Ullrich JE, et al. Thrombospondin-1 is a major activator of TGFbeta 1 in vivo. Cell 1998; 93:1159–1170.PubMedCrossRefGoogle Scholar
  6. 6.
    Brown CB, Boyer AS, Runyan RB, Barnett JV. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science 1999; 283:2080–2082.PubMedCrossRefGoogle Scholar
  7. 7.
    Deng X, Bellis S, Yan Z, Friedman E. Differential responsiveness to autocrine and exogenous transforming growth factor (TGF) betal in cells with nonfunctional TGF-beta receptor type III. Cell Growth Differ 1999; 10:11–18.PubMedGoogle Scholar
  8. 8.
    Blobe GC, Schiemann WP, Pepin MC, et al. Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling. J Biol Chem 2001; 276:24627–24637.PubMedCrossRefGoogle Scholar
  9. 9.
    Blobe GC, Liu X, Fang SJ, How T, Lodish HF. A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling. functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC. J Biol Chem 2001; 276:39608–39617.PubMedCrossRefGoogle Scholar
  10. 10.
    Eickelberg O, Centrella M, Reiss M, Kashgarian M, Wells RG. Betaglycan inhibits TGF-beta signaling by preventing type I/type II receptor complex formation: glycosaminoglycan modifications alter betaglycan function. J Biol Chem 2002; 277:823–829.PubMedCrossRefGoogle Scholar
  11. 11.
    Piek E, Heldin CH, Ten Dijke P. Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J 1999: 13:2105–2124.PubMedGoogle Scholar
  12. 12.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massague J. Mechanism of activation of the TGF-beta receptor. Nature 1994; 370:341–347.PubMedCrossRefGoogle Scholar
  13. 13.
    Nakao A, Imamura T, Souchelnytskyi S, et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J 1997; 16:5353–5362.PubMedCrossRefGoogle Scholar
  14. 14.
    Brandes ME, Allen JB, Ogawa Y, Wahl SM. Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals. J Clin Invest 1991: 87:1108–1113.PubMedCrossRefGoogle Scholar
  15. 15.
    Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol 1998; 16:137–161.PubMedCrossRefGoogle Scholar
  16. 16.
    Kehrl JH, Wakefield LM, Roberts AB, et al. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 1986; 163:1037–1050.PubMedCrossRefGoogle Scholar
  17. 17.
    Gorelik L, Flavell RA. Transforming growth factor-beta in T cell biology. Nature Rev Immunol 2002; 2:46–53.CrossRefGoogle Scholar
  18. 18.
    Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001; 194:629–644.PubMedCrossRefGoogle Scholar
  19. 19.
    Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359:693–699.PubMedCrossRefGoogle Scholar
  20. 20.
    Nakao A, Miike S, Hatano M, et al. Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med 2000; 192:151–158.PubMedCrossRefGoogle Scholar
  21. 21.
    Lucas PJ, Kim SJ, Melby SJ, Gress RE. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor. J Exp Med 2000; 191:1187–1196.PubMedCrossRefGoogle Scholar
  22. 22.
    Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000; 12:171–181.PubMedCrossRefGoogle Scholar
  23. 23.
    Bogdan C, Paik J, Vodovotz Y, Nathan C. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 1992; 267:23301–23308.PubMedGoogle Scholar
  24. 24.
    Riedl E, Strobl H, Majdic O, Knapp W. TGF-beta 1 promotes in vitro generation of dendritic cells by protectingprogenitor cells from apoptosis. J Immunol 1997; 158:1591–1597.PubMedGoogle Scholar
  25. 25.
    Geissmann F, Revy P, Regnault A, et al. TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 1999; 162:4567–4575.PubMedGoogle Scholar
  26. 26.
    Borkowski TA, Letterio JJ, Farr AG, Udey MC. A role for endogenous transforming growth factor beta 1 in Langerhans cell biology: the skin of transforming growth factor beta 1 null mice is devoid of epidermal Langerhans cells. J Exp Med 1996; 184:2417–2422.PubMedCrossRefGoogle Scholar
  27. 27.
    Torre-Amione G, Beauchamp RD, Koeppen H, et al. A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc Natl Acad Sci USA 1990; 87:1486–1490.CrossRefGoogle Scholar
  28. 28.
    Arteaga CL, Carty-Dugger T, Moses HL, Hurd SD, Pietenpol JA. Transforming growth factor beta 1 can induce estrogen-independent tumorigenicity of human breast cancer cells in athymic mice. Cell Growth Differ 1993; 4:193–201.PubMedGoogle Scholar
  29. 29.
    Wieser R, Attisano L, Wrana JL, Massague J. Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region. Mol Cell Biol 1993; 13:7239–7247.PubMedGoogle Scholar
  30. 30.
    Maeda H, Shiraishi A. TGF-beta contributes to the shift toward Th2-type responses through direct and IL-10-mediated pathways in tumor-bearing mice. J Immunol 1996; 156:73–78.PubMedGoogle Scholar
  31. 31.
    Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT. Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J Clin Invest 1993; 92:2569–2576.PubMedCrossRefGoogle Scholar
  32. 32.
    Wojtowicz-Praga S, Verma UN, Wakefield L, et al. Modulation of B16 melanoma growth and metastasis by anti-transforming growth factor beta antibody and interleukin-2. J Immunother Emphasis Tumor Immunol 1996; 19:169–175.PubMedCrossRefGoogle Scholar
  33. 33.
    Fakhrai H, Dorigo O, Shawler DL, et al. Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci USA 1996; 93:2909–2914.PubMedCrossRefGoogle Scholar
  34. 34.
    Matthews E, Yang T, Janulis L, et al. Down-regulation of TGF-beta 1 production restores immunogenicity in prostate cancer cells. Br J Cancer 2000; 83:519–525.PubMedCrossRefGoogle Scholar
  35. 35.
    Won J, Kim H, Park EJ, Hong Y, Kim SJ, Yun Y. Tumorigenicity of mouse thymoma is suppressed by soluble type II transforming growth factor beta receptor therapy. Cancer Res 1999; 59:1273–1277.PubMedGoogle Scholar
  36. 36.
    Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001; 7:1118–1122.PubMedCrossRefGoogle Scholar
  37. 37.
    Campbell JD, Cook G, Robertson SE, et al. Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF beta is reversed by IL-15. J Immunol 2001; 167:553–561.PubMedGoogle Scholar
  38. 38.
    Wu SP, Sun LZ, Willson JK, Humphrey L, Kerbel R, Brattain MG. Repression of autocrine transforming growth factor beta 1 and beta 2 in quiescent CBS colon carcinoma cells leads to progression of tumorigenic properties. Cell Growth Differ 1993; 4:115–123.PubMedGoogle Scholar
  39. 39.
    McInnes IB, Liew FY. Interleukin 15: a proinflammatory role in rheumatoid arthritis synovitis. Immunol Today 1998; 19:75–79.PubMedCrossRefGoogle Scholar
  40. 40.
    Bosher JM, Labouesse M. RNA interference: genetic wand and genetic watchdog. Nat Cell Biol 2000; 2:E31–E36.PubMedCrossRefGoogle Scholar
  41. 41.
    Yang X, Letterio JJ, Lechleider RJ, et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J 1999; 18:1280–1291.PubMedCrossRefGoogle Scholar
  42. 42.
    Lopez-Casillas F, Payne HM, Andres JL, Massague J. Betaglycan can act as a dual modulator of TGFbeta access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol 1994; 124:557–568.PubMedCrossRefGoogle Scholar
  43. 43.
    Bandyopadhyay A, Lopez-Casillas F, Malik SN, et al. Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 2002; 62:4690–4695.PubMedGoogle Scholar
  44. 44.
    Huber D, Philipp J, Fontana A. Protease inhibitors interfere with the transforming growth factor-betadependent but not the transforming growth factor-beta-independent pathway of tumor cell-mediated immunosuppression. J Immunol 1992; 148:277–284.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  • Gerard C. Blobe

There are no affiliations available

Personalised recommendations