Cancer Microenvironment

, Volume 3, Issue 1, pp 29–47 | Cite as

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

  • Jennifer L. Barnas
  • Michelle R. Simpson-Abelson
  • Sandra J. Yokota
  • Raymond J. KelleherJr.
  • Richard B. BankertEmail author
Review Paper


The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.


Cancer Fibroblast Immunotherapy Stromal cell T lymphocyte TCR signal transduction Tumor microenvironment Xenograft model 



dendritic cell


tumor-associated fibroblast


myeloid-derived suppressor cell


mesenchymal stem cell


tumor-infiltrating T cells


T cell receptor


Transforming growth factor-β1



This work was supported by National Institute of Health grants R01CA108970, R01CA131407, and R56AI079188.


  1. 1.
    Berd D, Mastrangelo MJ, Lattime E, Sato T, Maguire HC Jr (1996) Melanoma and vitiligo: immunology’s Grecian urn. Cancer Immunol Immunother 42:263–267PubMedCrossRefGoogle Scholar
  2. 2.
    Barnhill RL, Mihm MC (1992) Histopathology of malignant melanoma and its precursor lesions. In: Balch CM, Houghton AN, Milton GW, Sober AJ, Soong S (eds) Cutaneous melanoma, 2nd edn. JB Lippincott, OxfordGoogle Scholar
  3. 3.
    Balch CM, Soong S, Shaw HM, Urist MM, McCarthy WH (1992) An analysis of prognostic factors in 8500 patients with cutaneous melanoma. In: Balch CM, Houghton AN, Milton GW, Sober AJ, Soong S (eds) cutaneous melanoma, 2nd edn. JB Lippincott, OxfordGoogle Scholar
  4. 4.
    Cook MG (1992) The significance of inflammation and regression in melanoma. Virchows Arch A Pathol Anat Histopathol 420:113–115PubMedCrossRefGoogle Scholar
  5. 5.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964PubMedCrossRefGoogle Scholar
  6. 6.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998PubMedCrossRefGoogle Scholar
  7. 7.
    Smyth MJ, Godfrey DI, Trapani JA (2001) A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2:293–299PubMedCrossRefGoogle Scholar
  8. 8.
    Melief CJ, Toes RE, Medema JP, van der Burg SH, Ossendorp F, Offringa R (2000) Strategies for immunotherapy of cancer. Adv Immunol 75:235–282PubMedCrossRefGoogle Scholar
  9. 9.
    Pardoll D (2003) Does the immune system see tumors as foreign or self? Annu Rev Immunol 21:807–839PubMedCrossRefGoogle Scholar
  10. 10.
    Finn OJ (2003) Cancer vaccines: between the idea and the reality. Nat Rev Immunol 3:630–641PubMedCrossRefGoogle Scholar
  11. 11.
    Khong HT, Restifo NP (2002) Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat immunol 3:999–1005PubMedCrossRefGoogle Scholar
  12. 12.
    Gilboa E (2004) The promise of cancer vaccines. Nat Rev Cancer 4:401–411PubMedCrossRefGoogle Scholar
  13. 13.
    Odunsi K, Jungbluth AA, Stockert E, Qian F, Gnjatic S, Tammela J, Intengan M, Beck A, Keitz B, Santiago D, Williamson B, Scanlan MJ, Ritter G, Chen YT, Driscoll D, Sood A, Lele S, Old LJ (2003) NY-ESO-1 and LAGE-1 cancer-testis antigens are potential targets for immunotherapy in epithelial ovarian cancer. Cancer Res 63:6076–6083PubMedGoogle Scholar
  14. 14.
    Jager E, Karbach J, Gnjatic S, Neumann A, Bender A, Valmori D, Ayyoub M, Ritter E, Ritter G, Jager D, Panicali D, Hoffman E, Pan L, Oettgen H, Old LJ, Knuth A (2006) Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients. Proc Natl Acad Sci USA 103:14453–14458PubMedCrossRefGoogle Scholar
  15. 15.
    Valmori D, Souleimanian NE, Tosello V, Bhardwaj N, Adams S, O’Neill D, Pavlick A, Escalon JB, Cruz CM, Angiulli A, Angiulli F, Mears G, Vogel SM, Pan L, Jungbluth AA, Hoffmann EW, Venhaus R, Ritter G, Old LJ, Ayyoub M (2007) Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. Proc Natl Acad Sci USA 104:8947–8952PubMedCrossRefGoogle Scholar
  16. 16.
    Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263–274PubMedCrossRefGoogle Scholar
  17. 17.
    Chiou SH, Sheu BC, Chang WC, Huang SC, Hong-Nerng H (2005) Current concepts of tumor-infiltrating lymphocytes in human malignancies. J Reprod Immunol 67:35–50PubMedCrossRefGoogle Scholar
  18. 18.
    Rangarajan A, Weinberg RA (2003) Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 3:952–959PubMedCrossRefGoogle Scholar
  19. 19.
    Steinman RM, Mellman I (2004) Immunotherapy: bewitched, bothered, and bewildered no more. Science 305:197–200PubMedCrossRefGoogle Scholar
  20. 20.
    Broderick L, Bankert RB (2006) Membrane-associated TGF-beta1 inhibits human memory T cell signaling in malignant and nonmalignant inflammatory microenvironments. J Immunol 177:3082–3088PubMedGoogle Scholar
  21. 21.
    Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738PubMedGoogle Scholar
  22. 22.
    Schreiber H, Rowley DA (1999) Inflammation and cancer. In: Gallin JI, Smyderman R (eds) Inflammation: basic principles and clinical correlates, 3rd edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  23. 23.
    Broderick L, Yokota SJ, Reineke J, Mathiowitz E, Stewart CC, Barcos M, Kelleher RJ Jr, Bankert RB (2005) Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activated by local delivery of IL-12 to proliferate, produce IFN-gamma, and eradicate tumor cells. J Immunol 174:898–906PubMedGoogle Scholar
  24. 24.
    Agrawal S, Marquet J, Delfau-Larue MH, Copie-Bergman C, Jouault H, Reyes F, Bensussan A, Farcet JP (1998) CD3 hyporesponsiveness and in vitro apoptosis are features of T cells from both malignant and nonmalignant secondary lymphoid organs. J Clin Invest 102:1715–1723PubMedCrossRefGoogle Scholar
  25. 25.
    Radoja S, Saio M, Schaer D, Koneru M, Vukmanovic S, Frey AB (2001) CD8(+) tumor-infiltrating T cells are deficient in perforin-mediated cytolytic activity due to defective microtubule-organizing center mobilization and lytic granule exocytosis. J Immunol 167:5042–5051PubMedGoogle Scholar
  26. 26.
    Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334PubMedCrossRefGoogle Scholar
  27. 27.
    Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811PubMedCrossRefGoogle Scholar
  28. 28.
    Shevach EM (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30:636–645PubMedCrossRefGoogle Scholar
  29. 29.
    Waldmann H, Cobbold S (2009) Regulatory T cells: context matters. Immunity 30:613–615PubMedCrossRefGoogle Scholar
  30. 30.
    Battaglia M, Roncarolo MG (2009) The fate of human Treg cells. Immunity 30:763–765PubMedCrossRefGoogle Scholar
  31. 31.
    Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30:899–911PubMedCrossRefGoogle Scholar
  32. 32.
    Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci 102:18538–18543PubMedCrossRefGoogle Scholar
  33. 33.
    Curiel T, Zou W, Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949Google Scholar
  34. 34.
    Hilchey SP, De A, Rimsza LM, Bankert RB, Bernstein SH (2007) Follicular lymphoma intratumoral CD4 + CD25 + GITR + regulatory T cells potently suppress CD3/CD28-costimulated autologous and allogeneic CD8 + CD25- and CD4 + CD25- T cells. J Immunol 178:4051–4061PubMedGoogle Scholar
  35. 35.
    Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMedGoogle Scholar
  36. 36.
    Wood KJ, Sakaguchi S (2003) Regulatory T cells in transplantation tolerance. Nat Rev Immunol 3:199–210PubMedCrossRefGoogle Scholar
  37. 37.
    von Herrath MG, Harrison LC (2003) Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 3:223–232CrossRefGoogle Scholar
  38. 38.
    Bach JF (2003) Regulatory T cells under scrutiny. Nat Rev Immunol 3:189–198PubMedCrossRefGoogle Scholar
  39. 39.
    Read S, Powrie F (2001) CD4(+) regulatory T cells. Curr Opin Immunol 13:644–649PubMedCrossRefGoogle Scholar
  40. 40.
    Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193:1303–1310PubMedCrossRefGoogle Scholar
  41. 41.
    Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD, Isaacs JD, Lechler RI (2001) Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood 98:2736–2744PubMedCrossRefGoogle Scholar
  42. 42.
    Levings MK, Sangregorio R, Roncarolo MG (2001) Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 193:1295–1302PubMedCrossRefGoogle Scholar
  43. 43.
    Boon T, Coulie PG, Van den Eynde BJ, van der Bruggen P (2006) Human T cell responses against melanoma. Annu Rev Immunol 24:175–208PubMedCrossRefGoogle Scholar
  44. 44.
    Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, Chang A, Zou W (2007) Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 178:6730–6733PubMedGoogle Scholar
  45. 45.
    Miyahara Y, Odunsi K, Chen W, Peng G, Matsuzaki J, Wang RF (2008) Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci USA 105:15505–15510PubMedCrossRefGoogle Scholar
  46. 46.
    Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, Chang A, Coukos G, Liu R, Zou W (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114:1141–1149PubMedCrossRefGoogle Scholar
  47. 47.
    Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852PubMedCrossRefGoogle Scholar
  48. 48.
    Chen Z, O’Shea JJ (2008) Regulation of IL-17 production in human lymphocytes. Cytokine 41:71–78PubMedCrossRefGoogle Scholar
  49. 49.
    Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361:888–898PubMedCrossRefGoogle Scholar
  50. 50.
    Gaffen SL (2009) Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 9:556–567PubMedCrossRefGoogle Scholar
  51. 51.
    Murugaiyan G, Saha B (2009) Protumor vs antitumor functions of IL-17. J Immunol 183:4169–4175PubMedCrossRefGoogle Scholar
  52. 52.
    Broderick L, Brooks SP, Takita H, Baer AN, Bernstein JM, Bankert RB (2006) IL-12 reverses anergy to T cell receptor triggering in human lung tumor-associated memory T cells. Clin Immunol 118:159–169PubMedCrossRefGoogle Scholar
  53. 53.
    Mizoguchi H, O’Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC (1992) Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258:1795–1798PubMedCrossRefGoogle Scholar
  54. 54.
    Whiteside T (2004) Down-Regulation of z-chain expression in T cells: a biomarker of prognosis of cancer? Cancer Immunol Immunother 53:865–878PubMedGoogle Scholar
  55. 55.
    Rodriguez PC, Ochoa AC (2006) T cell dysfunction in cancer: role of myeloid cells and tumor cells regulating amino acid availability and oxidative stress. Semin Cancer Biol 16:66–72PubMedCrossRefGoogle Scholar
  56. 56.
    Koneru M, Schaer D, Monu N, Ayala A, Frey AB (2005) Defective proximal TCR signaling inhibits CD8+ tumor-infiltrating lymphocyte lytic function. J Immunol 174:1830–1840PubMedGoogle Scholar
  57. 57.
    Kosugi A, Sakakura J, Yasuda K, Ogata M, Hamaoka T (2001) Involvement of SHP-1 tyrosine phosphatase in TCR-mediated signaling pathways in lipid rafts. Immunity 14:669–680PubMedCrossRefGoogle Scholar
  58. 58.
    Sathish JG, Dolton G, Leroy FG, Matthews RJ (2007) Loss of Src homology region 2 domain-containing protein tyrosine phosphatase-1 increases CD8+ T cell-APC conjugate formation and is associated with enhanced in vivo CTL function. J Immunol 178:330–337PubMedGoogle Scholar
  59. 59.
    Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL (2004) SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173:945–954PubMedGoogle Scholar
  60. 60.
    Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS, Routy JP, Haddad EK, Sekaly RP (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12:1198–1202PubMedCrossRefGoogle Scholar
  61. 61.
    Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cell during chronic viral infections. Nature 439:682–687PubMedCrossRefGoogle Scholar
  62. 62.
    Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 203:2223–2227PubMedCrossRefGoogle Scholar
  63. 63.
    Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, Kwon ED (2007) PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 13:1757–1761PubMedCrossRefGoogle Scholar
  64. 64.
    Nazareth MR, Broderick L, Simpson-Abelson MR, Kelleher RJ Jr, Yokota SJ, Bankert RB (2007) Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. J Immunol 178:5552–5562PubMedGoogle Scholar
  65. 65.
    Olenchock BA, Guo R, Carpenter JH, Jordan M, Topham MK, Koretzky GA, Zhong XP (2006) Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol 7:1174–1181PubMedCrossRefGoogle Scholar
  66. 66.
    Zha Y, Marks R, Ho AW, Peterson AC, Janardhan S, Brown I, Praveen K, Stang S, Stone JC, Gajewski TF (2006) T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha. Nat Immunol 7:1166–1173PubMedCrossRefGoogle Scholar
  67. 67.
    Uzzo RG, Rayman P, Kolenko V, Clark PE, Cathcart MK, Bloom T, Novick AC, Bukowski RM, Hamilton T, Finke JH (1999) Renal cell carcinoma-derived gangliosides suppress nuclear factor-kappaB activation in T cells. J Clin Invest 104:769–776PubMedCrossRefGoogle Scholar
  68. 68.
    Weil R, Israel A (2006) Deciphering the pathway from the TCR to NF-kappaB. Cell Death Differ 13:826–833PubMedCrossRefGoogle Scholar
  69. 69.
    Nel AE, Slaughter N (2002) T-cell activation through the antigen receptor. Part 2: role of signaling cascades in T-cell differentiation, anergy, immune senescence, and development of immunotherapy. J Allergy Clin Immunol 109:901–915PubMedCrossRefGoogle Scholar
  70. 70.
    Nel AE (2002) T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. J Allergy Clin Immunol 109:758–770PubMedCrossRefGoogle Scholar
  71. 71.
    Li MO, Sanjabi S, Wan YY, Robertson AL, Flavell RA (2006) Transforming growth factor-β of immune responses. Annu Rev Immunol 24:99–146PubMedCrossRefGoogle Scholar
  72. 72.
    Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90:770–774PubMedCrossRefGoogle Scholar
  73. 73.
    Letterio JJ, Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16:137–161PubMedCrossRefGoogle Scholar
  74. 74.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693–699PubMedCrossRefGoogle Scholar
  75. 75.
    Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-β and the immune response: implications for anticancer therapy. Clin Cancer Res 13:5262–5270PubMedCrossRefGoogle Scholar
  76. 76.
    Saunier EF, Akhurst RJ (2006) TGF beta inhibition for cancer therapy. Curr Cancer Drug Targets 6:565–578PubMedCrossRefGoogle Scholar
  77. 77.
    Ahmadzadeh M, Rosenberg SA (2005) TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol 174:5215–5223PubMedGoogle Scholar
  78. 78.
    Byrne SN, Knox MC, Halliday GM (2008) TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. Immunol Cell Biol 86:92–7Google Scholar
  79. 79.
    Chen CH, Seguin-Devaux C, Burke NA, Oriss TB, Watkins SC, Clipstone N, Ray A (2003) Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. J Exp Med 197:1689–1699PubMedCrossRefGoogle Scholar
  80. 80.
    Leivonen SK, Kahari VM (2007) Transforming growth factor-beta signaling in cancer invasion and metastasis. Int J Cancer 121:2119–2124PubMedCrossRefGoogle Scholar
  81. 81.
    Colombo MP, Trinchieri G (2002) Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev 13:155–168PubMedCrossRefGoogle Scholar
  82. 82.
    Del Vecchio M, Bajetta E, Canova S, Lotze MT, Wesa A, Parmiani G, Anichini A (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677–4685PubMedCrossRefGoogle Scholar
  83. 83.
    Yoo JK, Cho JH, Lee SW, Sung YC (2002) IL-12 provides proliferation and survival signals to murine CD4+ T cells through phosphatidylinositol 3-kinase/Akt signaling pathway. J Immunol 169:3637–3643PubMedGoogle Scholar
  84. 84.
    Tatsumi T, Takehara T, Yamaguchi S, Sasakawa A, Miyagi T, Jinushi M, Sakamori R, Kohga K, Uemura A, Ohkawa K, Storkus WJ, Hayashi N (2007) Injection of IL-12 gene-transduced dendritic cells into mouse liver tumor lesions activates both innate and acquired immunity. Gene Ther 14:863–871PubMedCrossRefGoogle Scholar
  85. 85.
    Simpson-Abelson M, Bankert RB (2008) Targeting the TCR signaling checkpoint: a therapeutic strategy to reactivate memory T cells in the tumor microenvironment. Expert Opin Ther Targets 12:477–490PubMedCrossRefGoogle Scholar
  86. 86.
    Egilmez NK, Hess SD, Chen FA, Takita H, Conway TF, Bankert RB (2002) Human CD4+ effector T cells mediate indirect interleukin-12- and interferon-gamma-dependent suppression of autologous HLA-negative lung tumor xenografts in severe combined immunodeficient mice. Cancer Res 62:2611–2617PubMedGoogle Scholar
  87. 87.
    Hess SD, Egilmez NK, Bailey N, Anderson TM, Mathiowitz E, Bernstein SH, Bankert RB (2003) Human CD4+ T cells present within the microenvironment of human lung tumors are mobilized by the local and sustained release of IL-12 to kill tumors in situ by indirect effects of IFN-gamma. J Immunol 170:400–412PubMedGoogle Scholar
  88. 88.
    Kilinc MO, Aulakh KS, Nair RE, Jones SA, Alard P, Kosiewicz MM, Egilmez NK (2006) Reversing tumor immune suppression with intratumoral IL-12: activation of tumor-associated T effector/memory cells, induction of T suppressor apoptosis, and infiltration of CD8+ T effectors. J Immunol 177:6962–6973PubMedGoogle Scholar
  89. 89.
    Tomlinson MG, Heath VL, Turck CW, Watson SP, Weiss A (2004) SHIP family inositol phosphatases interact with and negatively regulate the Tec tyrosine kinase. J Biol Chem 279:55089–55096PubMedCrossRefGoogle Scholar
  90. 90.
    Berg LJ, Finkelstein LD, Lucas JA, Schwartzberg PL (2005) Tec family kinases in T lymphocyte development and function. Annu Rev Immunol 23:549–600PubMedCrossRefGoogle Scholar
  91. 91.
    Markiewicz MA, Wise EL, Buchwald ZS, Cheney EE, Hansen TH, Suri A, Cemerski S, Allen PM, Shaw AS (2009) IL-12 enhances CTL synapse formation and induces self-reactivity. J Immunol 182:1351–1361PubMedGoogle Scholar
  92. 92.
    Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401PubMedCrossRefGoogle Scholar
  93. 93.
    Silzle T, Randolph GJ, Kreutz M, Kunz-Schughart LA (2004) The fibroblast: sentinel cell and local immune modulator in tumor tissue. Int J Cancer 108:173–180PubMedCrossRefGoogle Scholar
  94. 94.
    Baglole CJ, Ray DM, Bernstein SH, Feldon SE, Smith TJ, Sime PJ, Phipps RP (2006) More than structural cells, fibroblasts create and orchestrate the tumor microenvironment. Immunol Invest 35:297–325PubMedCrossRefGoogle Scholar
  95. 95.
    Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG (1995) Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130:393–405PubMedCrossRefGoogle Scholar
  96. 96.
    Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G (2007) The myofibroblast: one function, multiple origins. Am J Pathol 170:1807–1816PubMedCrossRefGoogle Scholar
  97. 97.
    Jones EA, Kinsey SE, English A, Jones RA, Straszynski L, Meredith DM, Markham AF, Jack A, Emery P, McGonagle D (2002) Isolation and characterization of bone marrow multipotential mesenchymal progenitor cells. Arthritis Rheum 46:3349–3360PubMedCrossRefGoogle Scholar
  98. 98.
    Boisvert M, Gendron S, Chetoui N, Aoudjit F (2007) Alpha2 beta1 integrin signaling augments T cell receptor-dependent production of interferon-gamma in human T cells. Mol Immunol 44:3732–3740PubMedCrossRefGoogle Scholar
  99. 99.
    Sturm A, Krivacic KA, Fiocchi C, Levine AD (2004) Dual function of the extracellular matrix: stimulatory for cell cycle progression of naive T cells and antiapoptotic for tissue-derived memory T cells. J Immunol 173:3889–3900PubMedGoogle Scholar
  100. 100.
    Davis LS, Oppenheimer-Marks N, Bednarczyk JL, McIntyre BW, Lipsky PE (1990) Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules. J Immunol 145:785–793PubMedGoogle Scholar
  101. 101.
    Rao WH, Hales JM, Camp RD (2000) Potent costimulation of effector T lymphocytes by human collagen type I. J Immunol 165:4935–4940PubMedGoogle Scholar
  102. 102.
    Jones S, Horwood N, Cope A, Dazzi F (2007) The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells. J Immunol 179:2824–2831PubMedGoogle Scholar
  103. 103.
    Bocelli-Tyndall C, Barbero A, Candrian C, Ceredig R, Tyndall A, Martin I (2006) Human articular chondrocytes suppress in vitro proliferation of anti-CD3 activated peripheral blood mononuclear cells. J Cell Physiol 209:732–734PubMedCrossRefGoogle Scholar
  104. 104.
    Haniffa MA, Wang XN, Holtick U, Rae M, Isaacs JD, Dickinson AM, Hilkens CM, Collin MP (2007) Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol 179:1595–1604PubMedGoogle Scholar
  105. 105.
    English K, Barry FP, Field-Corbett CP, Mahon BP (2007) IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett 110:91–100PubMedCrossRefGoogle Scholar
  106. 106.
    Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761PubMedCrossRefGoogle Scholar
  107. 107.
    Pinchuk IV, Saada JI, Beswick EJ, Boya G, Qiu SM, Mifflin RC, Raju GS, Reyes VE, Powell DW (2008) PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. Gastroenterology 135:1228–1237, 1237.e1–2PubMedCrossRefGoogle Scholar
  108. 108.
    Lee SK, Seo SH, Kim BS, Kim CD, Lee JH, Kang JS, Maeng PJ, Lim JS (2005) IFN-gamma regulates the expression of B7-H1 in dermal fibroblast cells. J Dermatol Sci 40:95–103PubMedCrossRefGoogle Scholar
  109. 109.
    Young E, Stark WJ (1988) In vitro immunological function of human corneal fibroblasts. Invest Ophthalmol Vis Sci 29:1402–1406PubMedGoogle Scholar
  110. 110.
    Filer A, Parsonage G, Smith E, Osborne C, Thomas AM, Curnow SJ, Rainger GE, Raza K, Nash GB, Lord J, Salmon M, Buckley CD (2006) Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils. Arthritis Rheum 54:2096–2108PubMedCrossRefGoogle Scholar
  111. 111.
    Nanki T, Nagasaka K, Hayashida K, Saita Y, Miyasaka N (2001) Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol 167:5381–5385PubMedGoogle Scholar
  112. 112.
    Georganas C, Liu H, Perlman H, Hoffmann A, Thimmapaya B, Pope RM (2000) Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun. J Immunol 165:7199–7206PubMedGoogle Scholar
  113. 113.
    Bombara MP, Webb DL, Conrad P, Marlor CW, Sarr T, Ranges GE, Aune TM, Greve JM, Blue ML (1993) Cell contact between T cells and synovial fibroblasts causes induction of adhesion molecules and cytokines. J Leukoc Biol 54:399–406PubMedGoogle Scholar
  114. 114.
    Thiele K, Riemann D, Navarrete Santos A, Langner J, Kehlen A (2000) Cell-cell contact of human T cells with fibroblasts changes lymphocytic mRNA expression: increased mRNA expression of interleukin-17 and interleukin-17 receptor. Eur Cytokine Netw 11:53–58PubMedGoogle Scholar
  115. 115.
    Sporri B, Bickel M, Limat A, Waelti ER, Hunziker T, Wiesmann UN (1997) Autologous versus allogeneic T cell-stimulated IL-6 production by dermal fibroblasts. Inflammation 21:371–378PubMedCrossRefGoogle Scholar
  116. 116.
    Akashi M, Loussararian AH, Adelman DC, Saito M, Koeffler HP (1990) Role of lymphotoxin in expression of interleukin 6 in human fibroblasts. Stimulation and regulation. J Clin Invest 85:121–129PubMedCrossRefGoogle Scholar
  117. 117.
    Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, Kim HY (2004) IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways. Arthritis Res Ther 6:R120–R128PubMedCrossRefGoogle Scholar
  118. 118.
    Miranda-Carus ME, Balsa A, Benito-Miguel M, Perez de Ayala C, Martin-Mola E (2004) IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis: effect of methotrexate. J Immunol 173:1463–1476PubMedGoogle Scholar
  119. 119.
    Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, McKenzie BS, Kastelein RA, Cua DJ, de Waal MR (2009) Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med 206:535–548PubMedCrossRefGoogle Scholar
  120. 120.
    Yamamura Y, Gupta R, Morita Y, He X, Pai R, Endres J, Freiberg A, Chung K, Fox DA (2001) Effector function of resting T cells: activation of synovial fibroblasts. J Immunol 166:2270–2275PubMedGoogle Scholar
  121. 121.
    Yarovinsky TO, Hunninghake GW (2001) Lung fibroblasts inhibit activation-induced death of T cells through PGE(2)-dependent mechanisms. Am J Physiol Lung Cell Mol Physiol 281:L1248–L1256PubMedGoogle Scholar
  122. 122.
    Pilling D, Akbar AN, Girdlestone J, Orteu CH, Borthwick NJ, Amft N, Scheel-Toellner D, Buckley CD, Salmon M (1999) Interferon-beta mediates stromal cell rescue of T cells from apoptosis. Eur J Immunol 29:1041–1050PubMedCrossRefGoogle Scholar
  123. 123.
    Ayroldi E, Zollo O, Cannarile L, DA F, Grohmann U, Delfino DV, Riccardi C (1998) Interleukin-6 (IL-6) prevents activation-induced cell death: IL-2-independent inhibition of Fas/fasL expression and cell death. Blood 92:4212–4219PubMedGoogle Scholar
  124. 124.
    Taub DD, Turcovski-Corrales SM, Key ML, Longo DL, Murphy WJ (1996) Chemokines and T lymphocyte activation: I. Beta chemokines costimulate human T lymphocyte activation in vitro. J Immunol 156:2095–2103PubMedGoogle Scholar
  125. 125.
    McGettrick HM, Smith E, Filer A, Kissane S, Salmon M, Buckley CD, Rainger GE, Nash GB (2009) Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells. Eur J Immunol 39:113–125PubMedCrossRefGoogle Scholar
  126. 126.
    Williams SS, Chen FA, Kida H, Yokata S, Miya K, Kato M, Barcos MP, Wang HQ, Alosco T, Umemoto T, Croy BA, Repasky EA, Bankert RB (1996) Engraftment of human tumor-infiltrating lymphocytes and the production of anti-tumor antibodies in SCID mice. J Immunol 156:1908–1915PubMedGoogle Scholar
  127. 127.
    Simpson-Abelson MR, Purohit VS, Pang WM, Iyer V, Odunsi K, Demmy TL, Yokota SJ, Loyall JL, Kelleher RJ Jr, Balu-Iyer S, Bankert RB (2009) IL-12 delivered intratumorally by multilamellar liposomes reactivates memory T cells in human tumor microenvironments. Clin Immunol 132:71–82PubMedCrossRefGoogle Scholar
  128. 128.
    Bankert RB, Egilmez NK, Hess SD (2001) Human-SCID mouse chimeric models for the evaluation of anti-cancer therapies. Trends Immunol 22:386–393PubMedCrossRefGoogle Scholar
  129. 129.
    Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7:118–130PubMedCrossRefGoogle Scholar
  130. 130.
    Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R (2005) Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174:6477–6489PubMedGoogle Scholar
  131. 131.
    Sugamura K, Asao H, Kondo M, Tanaka N, Ishii N, Ohbo K, Nakamura M, Takeshita T (1996) The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu Rev Immunol 14:179–205PubMedCrossRefGoogle Scholar
  132. 132.
    Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (2001) Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol 167:1–5PubMedGoogle Scholar
  133. 133.
    Shultz LD, Pearson T, King M, Giassi L, Carney L, Gott B, Lyons B, Rossini AA, Greiner DL (2007) Humanized NOD/LtSz-scid IL2 receptor common gamma chain knockout mice in diabetes research. Ann N Y Acad Sci 1103:77–89PubMedCrossRefGoogle Scholar
  134. 134.
    Simpson-Abelson MR, Sonnenberg GF, Takita H, Yokota SJ, Conway TF Jr, Kelleher RJ Jr, Shultz LD, Barcos M, Bankert RB (2008) Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice. J Immunol 180:7009–7018PubMedGoogle Scholar
  135. 135.
    Ito A, Ishida T, Yano H, Inagaki A, Suzuki S, Sato F, Takino H, Mori F, Ri M, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R (2009) Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. Cancer Immunol Immunother 58:1195–1206PubMedCrossRefGoogle Scholar
  136. 136.
    Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan DF, Albelda SM, Carroll RG, Riley JL, Pastan I, June CH (2009) Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA 106:3360–3365PubMedCrossRefGoogle Scholar
  137. 137.
    Jaiswal S, Pearson T, Friberg H, Shultz LD, Greiner DL, Rothman AL, Mathew A (2009) Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice. PLoS ONE 4:e7251PubMedCrossRefGoogle Scholar
  138. 138.
    Bousso P, Robey EA (2004) Dynamic behavior of T cells and thymocytes in lymphoid organs as revealed by two-photon microscopy. Immunity 21:349–355PubMedCrossRefGoogle Scholar
  139. 139.
    Hugues S, Fetler L, Bonifaz L, Helft J, Amblard F, Amigorena S (2004) Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nat immunol 5:1235–1242PubMedCrossRefGoogle Scholar
  140. 140.
    Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, Sosman JA, Dutcher JP, Vogelzang NJ, Ryan JL (1997) Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood 90:2541–2548PubMedGoogle Scholar
  141. 141.
    Hill HC, Conway TF Jr, Sabel MS, Jong YS, Mathiowitz E, Bankert RB, Egilmez NK (2002) Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease. Cancer Res 62:7254–7263PubMedGoogle Scholar
  142. 142.
    Nair RE, Jong YS, Jones SA, Sharma A, Mathiowitz E, Egilmez NK (2006) IL-12 + GM-CSF microsphere therapy induces eradication of advanced spontaneous tumors in her-2/neu transgenic mice but fails to achieve long-term cure due to the inability to maintain effector T-cell activity. J Immunother 29:10–20PubMedCrossRefGoogle Scholar
  143. 143.
    Broderick L, Bankert RB (2006) Memory T cells in human tumor and chronic inflammatory microenvironments: sleeping beauties re-awakened by a cytokine kiss. Immunol Invest 35:419–436PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Jennifer L. Barnas
    • 1
  • Michelle R. Simpson-Abelson
    • 1
  • Sandra J. Yokota
    • 1
  • Raymond J. KelleherJr.
    • 1
  • Richard B. Bankert
    • 1
    Email author
  1. 1.Department of Microbiology and Immunology, Witebsky Center, School of Medicine and Biomedical SciencesUniversity at Buffalo, The State University of New YorkBuffaloUSA

Personalised recommendations