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Role of Cytokines in Tumor Immunity and Immune Tolerance to Cancer

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Cancer Immunology

Abstract

The complex cytokine network within the tumor microenvironment allows the coordinated, effective development of both innate and adaptive antitumor immune responses. While certain cytokines produced in the tumor microenvironment can inhibit tumor growth, others promote tumor growth and progression. Here, we review the roles of antitumor cytokines (IL-12 and IL-27) with potential preclinical and clinical applications, as well highlight pro-tumor cytokines (TGF-β, IL-17, IL-23, IL-35, and IL-10) with pathogenic significance in cancer progression. A more thorough understanding of tumor-cytokine and immune cell interactions in the tumor microenvironment, and thoughtful manipulation of the balance of pro- vs. anti-tumor cytokines, may pave the way for more effective cancer immunotherapeutic strategies.

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References

  1. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.

    Article  CAS  PubMed  Google Scholar 

  2. Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 2003;21:807–39.

    Article  CAS  PubMed  Google Scholar 

  3. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–71.

    Article  CAS  PubMed  Google Scholar 

  4. Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 2010;29(8):1093–102.

    Article  CAS  PubMed  Google Scholar 

  5. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  6. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.

    Article  CAS  PubMed  Google Scholar 

  7. Mattarollo SR, Smyth MJ. A novel axis of innate immunity in cancer. Nat Immunol. 2010;11(11):981–2.

    Article  CAS  PubMed  Google Scholar 

  8. Wu J, Lanier LL. Natural killer cells and cancer. Adv Cancer Res. 2003;90:127–56.

    Article  CAS  PubMed  Google Scholar 

  9. Srivastava P. Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol. 2002;20:395–425.

    Article  CAS  PubMed  Google Scholar 

  10. Shurin MR. Dendritic cells presenting tumor antigen. Cancer Immunol Immunother. 1996;43(3):158–64.

    Article  CAS  PubMed  Google Scholar 

  11. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105(1):93–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ladanyi A, Kiss J, Somlai B, Gilde K, Fejos Z, Mohos A, et al. Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother. 2007;56(9):1459–69.

    Article  PubMed  Google Scholar 

  15. Aras S, Zaidi MR. TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer. 2017;117(11):1583–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Panni RZ, Linehan DC, DeNardo DG. Targeting tumor-infiltrating macrophages to combat cancer. Immunotherapy. 2013;5(10):1075–87.

    Article  CAS  PubMed  Google Scholar 

  17. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer. 2004;4(1):11–22.

    Article  CAS  PubMed  Google Scholar 

  18. Smyth MJ, Cretney E, Kershaw MH, Hayakawa Y. Cytokines in cancer immunity and immunotherapy. Immunol Rev. 2004;202:275–93.

    Article  CAS  PubMed  Google Scholar 

  19. Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8(11):887–99.

    Article  CAS  PubMed  Google Scholar 

  20. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14(6):e218–28.

    Article  CAS  PubMed  Google Scholar 

  21. Belardelli F, Ferrantini M. Cytokines as a link between innate and adaptive antitumor immunity. Trends Immunol. 2002;23(4):201–8.

    Article  CAS  PubMed  Google Scholar 

  22. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993;14(7):335–8.

    Article  CAS  PubMed  Google Scholar 

  23. Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995;13:251–76.

    Article  CAS  PubMed  Google Scholar 

  24. Colombo MP, Trinchieri G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 2002;13(2):155–68.

    Article  CAS  PubMed  Google Scholar 

  25. Weiss JM, Subleski JJ, Wigginton JM, Wiltrout RH. Immunotherapy of cancer by IL-12-based cytokine combinations. Expert Opin Biol Ther. 2007;7(11):1705–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lasek W, Zagozdzon R, Jakobisiak M. Interleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol Immunother. 2014;63(5):419–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, et al. A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci U S A. 1996;93(24):14002–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jyothi MD, Khar A. Regulation of CD40L expression on natural killer cells by interleukin-12 and interferon gamma: its role in the elicitation of an effective antitumor immune response. Cancer Immunol Immunother. 2000;49(10):563–72.

    Article  CAS  PubMed  Google Scholar 

  29. Kodama T, Takeda K, Shimozato O, Hayakawa Y, Atsuta M, Kobayashi K, et al. Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12. Eur J Immunol. 1999;29(4):1390–6.

    Article  CAS  PubMed  Google Scholar 

  30. Smyth MJ, Crowe NY, Godfrey DI. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol. 2001;13(4):459–63.

    Article  CAS  PubMed  Google Scholar 

  31. Mariani E, Meneghetti A, Tarozzi A, Cattini L, Facchini A. Interleukin-12 induces efficient lysis of natural killer-sensitive and natural killer-resistant human osteosarcoma cells: the synergistic effect of interleukin-2. Scand J Immunol. 2000;51(6):618–25.

    Article  CAS  PubMed  Google Scholar 

  32. Robertson MJ, Cameron C, Atkins MB, Gordon MS, Lotze MT, Sherman ML, et al. Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer. Clin Cancer Res. 1999;5(1):9–16.

    CAS  PubMed  Google Scholar 

  33. Chouaib S, Chehimi J, Bani L, Genetet N, Tursz T, Gay F, et al. Interleukin 12 induces the differentiation of major histocompatibility complex class I-primed cytotoxic T-lymphocyte precursors into allospecific cytotoxic effectors. Proc Natl Acad Sci U S A. 1994;91(26):12659–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chiodoni C, Paglia P, Stoppacciaro A, Rodolfo M, Parenza M, Colombo MP. Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response. J Exp Med. 1999;190(1):125–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Toes RE, Schoenberger SP, van der Voort EI, Offringa R, Melief CJ. CD40-CD40Ligand interactions and their role in cytotoxic T lymphocyte priming and anti-tumor immunity. Semin Immunol. 1998;10(6):443–8.

    Article  CAS  PubMed  Google Scholar 

  36. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med. 1996;184(2):747–52.

    Article  CAS  PubMed  Google Scholar 

  37. Curtsinger JM, Johnson CM, Mescher MF. CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J Immunol. 2003;171(10):5165–71.

    Article  CAS  PubMed  Google Scholar 

  38. Curtsinger JM, Lins DC, Mescher MF. Signal 3 determines tolerance versus full activation of naive CD8 T cells: dissociating proliferation and development of effector function. J Exp Med. 2003;197(9):1141–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. van Mierlo GJ, den Boer AT, Medema JP, van der Voort EI, Fransen MF, Offringa R, et al. CD40 stimulation leads to effective therapy of CD40(-) tumors through induction of strong systemic cytotoxic T lymphocyte immunity. Proc Natl Acad Sci U S A. 2002;99(8):5561–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998;393(6684):480–3.

    Article  CAS  PubMed  Google Scholar 

  41. Brunda MJ, Luistro L, Warrier RR, Wright RB, Hubbard BR, Murphy M, et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993;178(4):1223–30.

    Article  CAS  PubMed  Google Scholar 

  42. Nastala CL, Edington HD, McKinney TG, Tahara H, Nalesnik MA, Brunda MJ, et al. Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol. 1994;153(4):1697–706.

    CAS  PubMed  Google Scholar 

  43. Hill HC, Conway TF Jr, Sabel MS, Jong YS, Mathiowitz E, Bankert RB, et al. 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. 2002;62(24):7254–63.

    CAS  PubMed  Google Scholar 

  44. Xiao Z, Casey KA, Jameson SC, Curtsinger JM, Mescher MF. Programming for CD8 T cell memory development requires IL-12 or type I IFN. J Immunol. 2009;182(5):2786–94.

    Article  CAS  PubMed  Google Scholar 

  45. Mortarini R, Borri A, Tragni G, Bersani I, Vegetti C, Bajetta E, et al. Peripheral burst of tumor-specific cytotoxic T lymphocytes and infiltration of metastatic lesions by memory CD8+ T cells in melanoma patients receiving interleukin 12. Cancer Res. 2000;60(13):3559–68.

    CAS  PubMed  Google Scholar 

  46. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010;28:445–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature. 1996;382(6587):174–7.

    Article  CAS  PubMed  Google Scholar 

  48. Ellyard JI, Simson L, Parish CR. Th2-mediated anti-tumour immunity: friend or foe? Tissue Antigens. 2007;70(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  49. Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One. 2009;4(11):e7965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Noguchi Y, Jungbluth A, Richards EC, Old LJ. Effect of interleukin 12 on tumor induction by 3-methylcholanthrene. Proc Natl Acad Sci U S A. 1996;93(21):11798–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Durali D, de Goer de Herve MG, Giron-Michel J, Azzarone B, Delfraissy JF, Taoufik Y. In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment. Blood. 2003;102(12):4084–9.

    Article  CAS  PubMed  Google Scholar 

  52. Adris S, Chuluyan E, Bravo A, Berenstein M, Klein S, Jasnis M, et al. Mice vaccination with interleukin 12-transduced colon cancer cells potentiates rejection of syngeneic non-organ-related tumor cells. Cancer Res. 2000;60(23):6696–703.

    CAS  PubMed  Google Scholar 

  53. Boggio K, Nicoletti G, Di Carlo E, Cavallo F, Landuzzi L, Melani C, et al. Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J Exp Med. 1998;188(3):589–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Robertson MJ, Ritz J. Interleukin 12: basic biology and potential applications in cancer treatment. Oncologist. 1996;1(1 & 2):88–97.

    CAS  PubMed  Google Scholar 

  55. Voest EE, Kenyon BM, O’Reilly MS, Truitt G, D’Amato RJ, Folkman J. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst. 1995;87(8):581–6.

    Article  CAS  PubMed  Google Scholar 

  56. Kocieda VP, Adhikary S, Emig F, Yen JH, Toscano MG, Ganea D. Prostaglandin E2-induced IL-23p19 subunit is regulated by cAMP-responsive element-binding protein and C/AATT enhancer-binding protein beta in bone marrow-derived dendritic cells. J Biol Chem. 2012;287(44):36922–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, et al. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med. 1995;182(1):155–62.

    Article  CAS  PubMed  Google Scholar 

  58. Angiolillo AL, Sgadari C, Tosato G. A role for the interferon-inducible protein 10 in inhibition of angiogenesis by interleukin-12. Ann N Y Acad Sci. 1996;795:158–67.

    Article  CAS  PubMed  Google Scholar 

  59. Kanegane C, Sgadari C, Kanegane H, Teruya-Feldstein J, Yao L, Gupta G, et al. Contribution of the CXC chemokines IP-10 and Mig to the antitumor effects of IL-12. J Leukoc Biol. 1998;64(3):384–92.

    Article  CAS  PubMed  Google Scholar 

  60. Lehtonen A, Lund R, Lahesmaa R, Julkunen I, Sareneva T, Matikainen S. IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells. Cytokine. 2003;24(3):81–90.

    Article  CAS  PubMed  Google Scholar 

  61. Bouker KB, Skaar TC, Riggins RB, Harburger DS, Fernandez DR, Zwart A, et al. Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis. Carcinogenesis. 2005;26(9):1527–35.

    Article  CAS  PubMed  Google Scholar 

  62. Bowie ML, Ibarra C, Seewalt VL. IRF-1 promotes apoptosis in p53-damaged basal-type human mammary epithelial cells: a model for early basal-type mammary carcinogenesis. Adv Exp Med Biol. 2008;617:367–74.

    Article  CAS  PubMed  Google Scholar 

  63. Acquaviva J, Chen X, Ren R. IRF-4 functions as a tumor suppressor in early B-cell development. Blood. 2008;112(9):3798–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pathak S, Ma S, Trinh L, Eudy J, Wagner KU, Joshi SS, et al. IRF4 is a suppressor of c-Myc induced B cell leukemia. PLoS One. 2011;6(7):e22628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yao L, Sgadari C, Furuke K, Bloom ET, Teruya-Feldstein J, Tosato G. Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12. Blood. 1999;93(5):1612–21.

    Article  CAS  PubMed  Google Scholar 

  66. Cavallo F, Quaglino E, Cifaldi L, Di Carlo E, Andre A, Bernabei P, et al. Interleukin 12-activated lymphocytes influence tumor genetic programs. Cancer Res. 2001;61(8):3518–23.

    CAS  PubMed  Google Scholar 

  67. Mitola S, Strasly M, Prato M, Ghia P, Bussolino F. IL-12 regulates an endothelial cell-lymphocyte network: effect on metalloproteinase-9 production. J Immunol. 2003;171(7):3725–33.

    Article  CAS  PubMed  Google Scholar 

  68. Ruegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ. Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med. 1998;4(4):408–14.

    Article  CAS  PubMed  Google Scholar 

  69. Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, et al. Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence. Nature. 2003;424(6948):516–23.

    Article  CAS  PubMed  Google Scholar 

  70. Watkins SK, Egilmez NK, Suttles J, Stout RD. IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol. 2007;178(3):1357–62.

    Article  CAS  PubMed  Google Scholar 

  71. Colombo MP, Piconese S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer. 2007;7(11):880–7.

    Article  CAS  PubMed  Google Scholar 

  72. Zou W. Regulatory T cells tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6(4):295–307.

    Article  CAS  PubMed  Google Scholar 

  73. Murugaiyan G, Martin S, Saha B. Levels of CD40 expression on dendritic cells dictate tumour growth or regression. Clin Exp Immunol. 2007;149(1):194–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Murugaiyan G, Agrawal R, Mishra GC, Mitra D, Saha B. Functional dichotomy in CD40 reciprocally regulates effector T cell functions. J Immunol. 2006;177(10):6642–9.

    Article  CAS  PubMed  Google Scholar 

  75. Murugaiyan G, Agrawal R, Mishra GC, Mitra D, Saha B. Differential CD40/CD40L expression results in counteracting antitumor immune responses. J Immunol. 2007;178(4):2047–55.

    Article  CAS  PubMed  Google Scholar 

  76. Mitsuhashi M, Liu J, Cao S, Shi X, Ma X. Regulation of interleukin-12 gene expression and its anti-tumor activities by prostaglandin E2 derived from mammary carcinomas. J Leukoc Biol. 2004;76(2):322–32.

    Article  CAS  PubMed  Google Scholar 

  77. Atkins MB, Robertson MJ, Gordon M, Lotze MT, DeCoste M, DuBois JS, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res. 1997;3(3):409–17.

    CAS  PubMed  Google Scholar 

  78. Portielje JE, Kruit WH, Schuler M, Beck J, Lamers CH, Stoter G, et al. Phase I study of subcutaneously administered recombinant human interleukin 12 in patients with advanced renal cell cancer. Clin Cancer Res. 1999;5(12):3983–9.

    CAS  PubMed  Google Scholar 

  79. Ansell SM, Geyer SM, Maurer MJ, Kurtin PJ, Micallef IN, Stella P, et al. Randomized phase II study of interleukin-12 in combination with rituximab in previously treated non-Hodgkin’s lymphoma patients. Clin Cancer Res. 2006;12(20 Pt 1):6056–63.

    Article  CAS  PubMed  Google Scholar 

  80. Younes A, Pro B, Robertson MJ, Flinn IW, Romaguera JE, Hagemeister F, et al. Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma and Hodgkin’s disease. Clin Cancer Res. 2004;10(16):5432–8.

    Article  CAS  PubMed  Google Scholar 

  81. Rook AH, Wood GS, Yoo EK, Elenitsas R, Kao DM, Sherman ML, et al. Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood. 1999;94(3):902–8.

    Article  CAS  PubMed  Google Scholar 

  82. Wilke CM, Wei S, Wang L, Kryczek I, Kao J, Zou W. Dual biological effects of the cytokines interleukin-10 and interferon-gamma. Cancer Immunol Immunother. 2011;60(11):1529–41.

    Article  CAS  PubMed  Google Scholar 

  83. Fallon JK, Vandeveer AJ, Schlom J, Greiner JW. Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody. Oncotarget. 2017;8(13):20558–71.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Murugaiyan G, Saha B. IL-27 in tumor immunity and immunotherapy. Trends Mol Med. 2013;19(2):108–16.

    Article  CAS  PubMed  Google Scholar 

  85. Murugaiyan G, Mittal A, Weiner HL. Identification of an IL-27/osteopontin axis in dendritic cells and its modulation by IFN-gamma limits IL-17-mediated autoimmune inflammation. Proc Natl Acad Sci U S A. 2010;107(25):11495–500.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Shinohara ML, Kim JH, Garcia VA, Cantor H. Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin. Immunity. 2008;29(1):68–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Schnurr M, Toy T, Shin A, Wagner M, Cebon J, Maraskovsky E. Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway. Blood. 2005;105(4):1582–9.

    Article  CAS  PubMed  Google Scholar 

  88. Pirhonen J, Siren J, Julkunen I, Matikainen S. IFN-alpha regulates Toll-like receptor-mediated IL-27 gene expression in human macrophages. J Leukoc Biol. 2007;82(5):1185–92.

    Article  CAS  PubMed  Google Scholar 

  89. Remoli ME, Gafa V, Giacomini E, Severa M, Lande R, Coccia EM. IFN-beta modulates the response to TLR stimulation in human DC: involvement of IFN regulatory factor-1 (IRF-1) in IL-27 gene expression. Eur J Immunol. 2007;37(12):3499–508.

    Article  CAS  PubMed  Google Scholar 

  90. Schuetze N, Schoeneberger S, Mueller U, Freudenberg MA, Alber G, Straubinger RK. IL-12 family members: differential kinetics of their TLR4-mediated induction by Salmonella enteritidis and the impact of IL-10 in bone marrow-derived macrophages. Int Immunol. 2005;17(5):649–59.

    Article  CAS  PubMed  Google Scholar 

  91. Liu L, Wang S, Shan B, Shao L, Sato A, Kawamura K, et al. IL-27-mediated activation of natural killer cells and inflammation produced antitumour effects for human oesophageal carcinoma cells. Scand J Immunol. 2008;68(1):22–9.

    Article  CAS  PubMed  Google Scholar 

  92. Morishima N, Owaki T, Asakawa M, Kamiya S, Mizuguchi J, Yoshimoto T. Augmentation of effector CD8+ T cell generation with enhanced granzyme B expression by IL-27. J Immunol. 2005;175(3):1686–93.

    Article  CAS  PubMed  Google Scholar 

  93. Schneider R, Yaneva T, Beauseigle D, El-Khoury L, Arbour N. IL-27 increases the proliferation and effector functions of human naive CD8+ T lymphocytes and promotes their development into Tc1 cells. Eur J Immunol. 2011;41(1):47–59.

    Article  CAS  PubMed  Google Scholar 

  94. Hisada M, Kamiya S, Fujita K, Belladonna ML, Aoki T, Koyanagi Y, et al. Potent antitumor activity of interleukin-27. Cancer Res. 2004;64(3):1152–6.

    Article  CAS  PubMed  Google Scholar 

  95. Salcedo R, Stauffer JK, Lincoln E, Back TC, Hixon JA, Hahn C, et al. IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells. J Immunol. 2004;173(12):7170–82.

    Article  CAS  PubMed  Google Scholar 

  96. Shinozaki Y, Wang S, Miyazaki Y, Miyazaki K, Yamada H, Yoshikai Y, et al. Tumor-specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti-tumor immunity. Int J Cancer. 2009;124(6):1372–8.

    Article  CAS  PubMed  Google Scholar 

  97. Wei J, Xia S, Sun H, Zhang S, Wang J, Zhao H, et al. Critical role of dendritic cell-derived IL-27 in antitumor immunity through regulating the recruitment and activation of NK and NKT cells. J Immunol. 2013;191(1):500–8.

    Article  CAS  PubMed  Google Scholar 

  98. Salcedo R, Hixon JA, Stauffer JK, Jalah R, Brooks AD, Khan T, et al. Immunologic and therapeutic synergy of IL-27 and IL-2: enhancement of T cell sensitization, tumor-specific CTL reactivity and complete regression of disseminated neuroblastoma metastases in the liver and bone marrow. J Immunol. 2009;182(7):4328–38.

    Article  CAS  PubMed  Google Scholar 

  99. Takeda A, Hamano S, Yamanaka A, Hanada T, Ishibashi T, Mak TW, et al. Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J Immunol. 2003;170(10):4886–90.

    Article  CAS  PubMed  Google Scholar 

  100. Kamiya S, Owaki T, Morishima N, Fukai F, Mizuguchi J, Yoshimoto T. An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+ T cells. J Immunol. 2004;173(6):3871–7.

    Article  CAS  PubMed  Google Scholar 

  101. Lucas S, Ghilardi N, Li J, de Sauvage FJ. IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci U S A. 2003;100(25):15047–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Artis D, Villarino A, Silverman M, He W, Thornton EM, Mu S, et al. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J Immunol. 2004;173(9):5626–34.

    Article  CAS  PubMed  Google Scholar 

  103. Yoshimoto T, Yoshimoto T, Yasuda K, Mizuguchi J, Nakanishi K. IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells: a novel therapeutic way for Th2-mediated allergic inflammation. J Immunol. 2007;179(7):4415–23.

    Article  CAS  PubMed  Google Scholar 

  104. Tassi E, Braga M, Longhi R, Gavazzi F, Parmiani G, Di Carlo V, et al. Non-redundant role for IL-12 and IL-27 in modulating Th2 polarization of carcinoembryonic antigen specific CD4 T cells from pancreatic cancer patients. PLoS One. 2009;4(10):e7234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Huber M, Steinwald V, Guralnik A, Brustle A, Kleemann P, Rosenplanter C, et al. IL-27 inhibits the development of regulatory T cells via STAT3. Int Immunol. 2008;20(2):223–34.

    Article  CAS  PubMed  Google Scholar 

  106. Wojno ED, Hosken N, Stumhofer JS, O’Hara AC, Mauldin E, Fang Q, et al. A role for IL-27 in limiting T regulatory cell populations. J Immunol. 2011;187(1):266–73.

    Article  CAS  PubMed  Google Scholar 

  107. Villarino AV, Stumhofer JS, Saris CJ, Kastelein RA, de Sauvage FJ, Hunter CA. IL-27 limits IL-2 production during Th1 differentiation. J Immunol. 2006;176(1):237–47.

    Article  CAS  PubMed  Google Scholar 

  108. Matsui M, Kishida T, Nakano H, Yoshimoto K, Shin-Ya M, Shimada T, et al. Interleukin-27 activates natural killer cells and suppresses NK-resistant head and neck squamous cell carcinoma through inducing antibody-dependent cellular cytotoxicity. Cancer Res. 2009;69(6):2523–30.

    Article  CAS  PubMed  Google Scholar 

  109. Yoshimoto T, Morishima N, Mizoguchi I, Shimizu M, Nagai H, Oniki S, et al. Antiproliferative activity of IL-27 on melanoma. J Immunol. 2008;180(10):6527–35.

    Article  CAS  PubMed  Google Scholar 

  110. Shimizu M, Shimamura M, Owaki T, Asakawa M, Fujita K, Kudo M, et al. Antiangiogenic and antitumor activities of IL-27. J Immunol. 2006;176(12):7317–24.

    Article  CAS  PubMed  Google Scholar 

  111. Feng XM, Chen XL, Liu N, Chen Z, Zhou YL, Han ZB, et al. Interleukin-27 upregulates major histocompatibility complex class II expression in primary human endothelial cells through induction of major histocompatibility complex class II transactivator. Hum Immunol. 2007;68(12):965–72.

    Article  CAS  PubMed  Google Scholar 

  112. Diveu C, McGeachy MJ, Boniface K, Stumhofer JS, Sathe M, Joyce-Shaikh B, et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J Immunol. 2009;182(9):5748–56.

    Article  CAS  PubMed  Google Scholar 

  113. Cocco C, Giuliani N, Di Carlo E, Ognio E, Storti P, Abeltino M, et al. Interleukin-27 acts as multifunctional antitumor agent in multiple myeloma. Clin Cancer Res. 2010;16(16):4188–97.

    Article  CAS  PubMed  Google Scholar 

  114. Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL. IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J Immunol. 2009;183(4):2435–43.

    Article  CAS  PubMed  Google Scholar 

  115. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol. 2006;7(9):937–45.

    Article  CAS  PubMed  Google Scholar 

  116. Sekar D, Hahn C, Brune B, Roberts E, Weigert A. Apoptotic tumor cells induce IL-27 release from human DCs to activate Treg cells that express CD69 and attenuate cytotoxicity. Eur J Immunol. 2012;42(6):1585–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol. 2009;10(9):981–91.

    Article  CAS  PubMed  Google Scholar 

  118. Shevde LA, Samant RS. Role of osteopontin in the pathophysiology of cancer. Matrix Biol. 2014;37:131–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Fabbi M, Carbotti G, Ferrini S. Dual roles of IL-27 in cancer biology and immunotherapy. Mediators Inflamm. 2017;2017:3958069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Oniki S, Nagai H, Horikawa T, Furukawa J, Belladonna ML, Yoshimoto T, et al. Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res. 2006;66(12):6395–404.

    Article  CAS  PubMed  Google Scholar 

  121. Massague J. TGFbeta in cancer. Cell. 2008;134(2):215–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010;10(8):554–67.

    Article  CAS  PubMed  Google Scholar 

  123. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700.

    Article  CAS  PubMed  Google Scholar 

  124. Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10(6):415–24.

    Article  CAS  PubMed  Google Scholar 

  125. Miettinen PJ, Ebner R, Lopez AR, Derynck R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol. 1994;127(6 Pt 2):2021–36.

    Article  CAS  PubMed  Google Scholar 

  126. Meulmeester E, Ten Dijke P. The dynamic roles of TGF-beta in cancer. J Pathol. 2011;223(2):205–18.

    Article  CAS  PubMed  Google Scholar 

  127. Bellone G, Aste-Amezaga M, Trinchieri G, Rodeck U. Regulation of NK cell functions by TGF-beta 1. J Immunol. 1995;155(3):1066–73.

    CAS  PubMed  Google Scholar 

  128. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, et al. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A. 2003;100(7):4120–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Liu C, Yu S, Kappes J, Wang J, Grizzle WE, Zinn KR, et al. Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood. 2007;109(10):4336–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Crane CA, Han SJ, Barry JJ, Ahn BJ, Lanier LL, Parsa AT. TGF-beta downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro Oncol. 2010;12(1):7–13.

    Article  CAS  PubMed  Google Scholar 

  131. Ruscetti F, Varesio L, Ochoa A, Ortaldo J. Pleiotropic effects of transforming growth factor-beta on cells of the immune system. Ann N Y Acad Sci. 1993;685:488–500.

    Article  CAS  PubMed  Google Scholar 

  132. Czarniecki CW, Chiu HH, Wong GH, McCabe SM, Palladino MA. Transforming growth factor-beta 1 modulates the expression of class II histocompatibility antigens on human cells. J Immunol. 1988;140(12):4217–23.

    CAS  PubMed  Google Scholar 

  133. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6(7):506–20.

    Article  CAS  PubMed  Google Scholar 

  134. Kobie JJ, Wu RS, Kurt RA, Lou S, Adelman MK, Whitesell LJ, et al. Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res. 2003;63(8):1860–4.

    CAS  PubMed  Google Scholar 

  135. Fainaru O, Woolf E, Lotem J, Yarmus M, Brenner O, Goldenberg D, et al. Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation. EMBO J. 2004;23(4):969–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ito M, Minamiya Y, Kawai H, Saito S, Saito H, Nakagawa T, et al. Tumor-derived TGFbeta-1 induces dendritic cell apoptosis in the sentinel lymph node. J Immunol. 2006;176(9):5637–43.

    Article  CAS  PubMed  Google Scholar 

  137. Huang A, Gilmour JW, Imami N, Amjadi P, Henderson DC, Allen-Mersh TG. Increased serum transforming growth factor-beta1 in human colorectal cancer correlates with reduced circulating dendritic cells and increased colonic Langerhans cell infiltration. Clin Exp Immunol. 2003;134(2):270–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013;23(3):277–86.

    Article  CAS  PubMed  Google Scholar 

  139. Goede V, Brogelli L, Ziche M, Augustin HG. Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1. Int J Cancer. 1999;82(5):765–70.

    Article  CAS  PubMed  Google Scholar 

  140. Hao NB, Lu MH, Fan YH, Cao YL, Zhang ZR, Yang SM. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol. 2012;2012:948098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55.

    Article  CAS  PubMed  Google Scholar 

  142. Lamagna C, Aurrand-Lions M, Imhof BA. Dual role of macrophages in tumor growth and angiogenesis. J Leukoc Biol. 2006;80(4):705–13.

    Article  CAS  PubMed  Google Scholar 

  143. Terabe M, Matsui S, Noben-Trauth N, Chen H, Watson C, Donaldson DD, et al. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol. 2000;1(6):515–20.

    Article  CAS  PubMed  Google Scholar 

  144. Fleming C, Morrissey S, Cai Y, Yan J. Gammadelta T cells: unexpected regulators of cancer development and progression. Trends Cancer. 2017;3(8):561–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Smyth MJ, Strobl SL, Young HA, Ortaldo JR, Ochoa AC. Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-beta. J Immunol. 1991;146(10):3289–97.

    CAS  PubMed  Google Scholar 

  146. Ranges GE, Figari IS, Espevik T, Palladino MA Jr. Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med. 1987;166(4):991–8.

    Article  CAS  PubMed  Google Scholar 

  147. Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8(5):369–80.

    Article  CAS  PubMed  Google Scholar 

  148. Gabriely G, da Cunha AP, Rezende RM, Kenyon B, Madi A, Vandeventer T, et al. Targeting latency-associated peptide promotes antitumor immunity. Sci Immunol. 2017;2(11).

    Google Scholar 

  149. McKarns SC, Schwartz RH, Kaminski NE. Smad3 is essential for TGF-beta 1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. J Immunol. 2004;172(7):4275–84.

    Article  CAS  PubMed  Google Scholar 

  150. Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell. 2008;134(3):392–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kaplan MH. Th9 cells: differentiation and disease. Immunol Rev. 2013;252(1):104–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol. 2008;9(12):1347–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Facciabene A, Motz GT, Coukos G. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res. 2012;72(9):2162–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, et al. Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 2002;168(9):4272–6.

    Article  CAS  PubMed  Google Scholar 

  155. Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol. 2008;20(2):241–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Liao D, Corle C, Seagroves TN, Johnson RS. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res. 2007;67(2):563–72.

    Article  CAS  PubMed  Google Scholar 

  157. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475(7355):226–30.

    Article  CAS  PubMed  Google Scholar 

  158. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.

    Article  CAS  PubMed  Google Scholar 

  159. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 2009;69(5):2000–9.

    Article  CAS  PubMed  Google Scholar 

  160. Giatromanolaki A, Bates GJ, Koukourakis MI, Sivridis E, Gatter KC, Harris AL, et al. The presence of tumor-infiltrating FOXP3+ lymphocytes correlates with intratumoral angiogenesis in endometrial cancer. Gynecol Oncol. 2008;110(2):216–21.

    Article  CAS  PubMed  Google Scholar 

  161. Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol. 2011;11(10):702–11.

    Article  CAS  PubMed  Google Scholar 

  162. Rech AJ, Vonderheide RH. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci. 2009;1174:99–106.

    Article  CAS  PubMed  Google Scholar 

  163. Callahan MK, Wolchok JD. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol. 2013;94(1):41–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015;125(9):3384–91.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Liu B, Song Y, Liu D. Recent development in clinical applications of PD-1 and PD-L1 antibodies for cancer immunotherapy. J Hematol Oncol. 2017;10(1):174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993;90(2):770–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992;359(6397):693–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther. 2015;9:4479–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One. 2014;9(3):e90353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Stevenson JP, Kindler HL, Papasavvas E, Sun J, Jacobs-Small M, Hull J, et al. Immunological effects of the TGFbeta-blocking antibody GC1008 in malignant pleural mesothelioma patients. Oncoimmunology. 2013;2(8):e26218.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Bogdahn U, Hau P, Stockhammer G, Venkataramana NK, Mahapatra AK, Suri A, et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 2011;13(1):132–42.

    Article  CAS  PubMed  Google Scholar 

  172. Nemunaitis J, Jahan T, Ross H, Sterman D, Richards D, Fox B, et al. Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX vaccine in advanced-stage non-small-cell lung cancer. Cancer Gene Ther. 2006;13(6):555–62.

    Article  CAS  PubMed  Google Scholar 

  173. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517.

    Article  CAS  PubMed  Google Scholar 

  174. Michel ML, Mendes-da-Cruz D, Keller AC, Lochner M, Schneider E, Dy M, et al. Critical role of ROR-gammat in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proc Natl Acad Sci U S A. 2008;105(50):19845–50.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Ciric B, El-behi M, Cabrera R, Zhang GX, Rostami A. IL-23 drives pathogenic IL-17-producing CD8+ T cells. J Immunol. 2009;182(9):5296–305.

    Article  CAS  PubMed  Google Scholar 

  176. O’Brien RL, Roark CL, Born WK. IL-17-producing gammadelta T cells. Eur J Immunol. 2009;39(3):662–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kim HY, Lee HJ, Chang YJ, Pichavant M, Shore SA, Fitzgerald KA, et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med. 2014;20(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  178. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.

    Article  CAS  PubMed  Google Scholar 

  179. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007;448(7152):480–3.

    Article  CAS  PubMed  Google Scholar 

  180. Murugaiyan G, Saha B. Protumor vs antitumor functions of IL-17. J Immunol. 2009;183(7):4169–75.

    Article  CAS  PubMed  Google Scholar 

  181. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–33.

    Article  CAS  PubMed  Google Scholar 

  182. Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA, et al. Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res. 2008;68(10):3915–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Shime H, Yabu M, Akazawa T, Kodama K, Matsumoto M, Seya T, et al. Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway. J Immunol. 2008;180(11):7175–83.

    Article  CAS  PubMed  Google Scholar 

  184. Murugaiyan G, Mittal A, Weiner HL. Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis. J Immunol. 2008;181(11):7480–8.

    Article  CAS  PubMed  Google Scholar 

  185. Chizzolini C, Chicheportiche R, Alvarez M, de Rham C, Roux-Lombard P, Ferrari-Lacraz S, et al. Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion. Blood. 2008;112(9):3696–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G. Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol. 2010;184(3):1630–41.

    Article  CAS  PubMed  Google Scholar 

  187. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204(12):2803–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009;114(6):1141–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Liu SJ, Tsai JP, Shen CR, Sher YP, Hsieh CL, Yeh YC, et al. Induction of a distinct CD8 Tnc17 subset by transforming growth factor-beta and interleukin-6. J Leukoc Biol. 2007;82(2):354–60.

    Article  CAS  PubMed  Google Scholar 

  190. Blankenstein T, Qin Z. The role of IFN-gamma in tumor transplantation immunity and inhibition of chemical carcinogenesis. Curr Opin Immunol. 2003;15(2):148–54.

    Article  CAS  PubMed  Google Scholar 

  191. Numasaki M, Watanabe M, Suzuki T, Takahashi H, Nakamura A, McAllister F, et al. IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol. 2005;175(9):6177–89.

    Article  CAS  PubMed  Google Scholar 

  192. Tartour E, Fossiez F, Joyeux I, Galinha A, Gey A, Claret E, et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res. 1999;59(15):3698–704.

    CAS  PubMed  Google Scholar 

  193. Numasaki M, Lotze MT, Sasaki H. Interleukin-17 augments tumor necrosis factor-alpha-induced elaboration of proangiogenic factors from fibroblasts. Immunol Lett. 2004;93(1):39–43.

    Article  CAS  PubMed  Google Scholar 

  194. Takahashi H, Numasaki M, Lotze MT, Sasaki H. Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol Lett. 2005;98(2):189–93.

    Article  CAS  PubMed  Google Scholar 

  195. Honorati MC, Neri S, Cattini L, Facchini A. Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthr Cartil. 2006;14(4):345–52.

    Article  CAS  Google Scholar 

  196. Jeon SH, Chae BC, Kim HA, Seo GY, Seo DW, Chun GT, et al. Mechanisms underlying TGF-beta1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis. J Leukoc Biol. 2007;81(2):557–66.

    Article  CAS  PubMed  Google Scholar 

  197. Huang X, Lee C. Regulation of stromal proliferation, growth arrest, differentiation and apoptosis in benign prostatic hyperplasia by TGF-beta. Front Biosci. 2003;8:s740–9.

    Article  CAS  PubMed  Google Scholar 

  198. Kehlen A, Thiele K, Riemann D, Rainov N, Langner J. Interleukin-17 stimulates the expression of IkappaB alpha mRNA and the secretion of IL-6 and IL-8 in glioblastoma cell lines. J Neuroimmunol. 1999;101(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  199. Aggarwal S, Gurney AL. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol. 2002;71(1):1–8.

    CAS  PubMed  Google Scholar 

  200. Lee JW, Wang P, Kattah MG, Youssef S, Steinman L, DeFea K, et al. Differential regulation of chemokines by IL-17 in colonic epithelial cells. J Immunol. 2008;181(9):6536–45.

    Article  CAS  PubMed  Google Scholar 

  201. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–59.

    Article  CAS  PubMed  Google Scholar 

  202. Subramaniam SV, Cooper RS, Adunyah SE. Evidence for the involvement of JAK/STAT pathway in the signaling mechanism of interleukin-17. Biochem Biophys Res Commun. 1999;262(1):14–9.

    Article  CAS  PubMed  Google Scholar 

  203. Shalom-Barak T, Quach J, Lotz M. Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB. J Biol Chem. 1998;273(42):27467–73.

    Article  CAS  PubMed  Google Scholar 

  204. Wang K, Kim MK, Di Caro G, Wong J, Shalapour S, Wan J, et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity. 2014;41(6):1052–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, Bothwell AL. Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci U S A. 2010;107(12):5540–4.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Zhang X, Wei L, Wang J, Qin Z, Wang J, Lu Y, et al. Suppression colitis and colitis-associated colon cancer by anti-S100a9 antibody in mice. Front Immunol. 2017;8:1774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009;206(7):1457–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood. 2008;112(2):362–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Hinrichs CS, Kaiser A, Paulos CM, Cassard L, Sanchez-Perez L, Heemskerk B, et al. Type 17 CD8+ T cells display enhanced antitumor immunity. Blood. 2009;114(3):596–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Benchetrit F, Ciree A, Vives V, Warnier G, Gey A, Sautes-Fridman C, et al. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood. 2002;99(6):2114–21.

    Article  CAS  PubMed  Google Scholar 

  211. Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha by human macrophages. J Immunol. 1998;160(7):3513–21.

    CAS  PubMed  Google Scholar 

  212. Gagnon J, Ramanathan S, Leblanc C, Cloutier A, McDonald PP, Ilangumaran S. IL-6, in synergy with IL-7 or IL-15, stimulates TCR-independent proliferation and functional differentiation of CD8+ T lymphocytes. J Immunol. 2008;180(12):7958–68.

    Article  CAS  PubMed  Google Scholar 

  213. Antonysamy MA, Fanslow WC, Fu F, Li W, Qian S, Troutt AB, et al. Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol. 1999;162(1):577–84.

    CAS  PubMed  Google Scholar 

  214. Hirahara N, Nio Y, Sasaki S, Minari Y, Takamura M, Iguchi C, et al. Inoculation of human interleukin-17 gene-transfected Meth-A fibrosarcoma cells induces T cell-dependent tumor-specific immunity in mice. Oncology. 2001;61(1):79–89.

    Article  CAS  PubMed  Google Scholar 

  215. Kryczek I, Wei S, Szeliga W, Vatan L, Zou W. Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood. 2009;114(2):357–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Vignali DA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012;13(8):722–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol. 2007;25:221–42.

    Article  CAS  PubMed  Google Scholar 

  218. Langowski JL, Kastelein RA, Oft M. Swords into plowshares: IL-23 repurposes tumor immune surveillance. Trends Immunol. 2007;28(5):207–12.

    Article  CAS  PubMed  Google Scholar 

  219. Qian X, Gu L, Ning H, Zhang Y, Hsueh EC, Fu M, et al. Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2. J Immunol. 2013;190(11):5894–902.

    Article  CAS  PubMed  Google Scholar 

  220. Poloso NJ, Urquhart P, Nicolaou A, Wang J, Woodward DF. PGE2 differentially regulates monocyte-derived dendritic cell cytokine responses depending on receptor usage (EP2/EP4). Mol Immunol. 2013;54(3-4):284–95.

    Article  CAS  PubMed  Google Scholar 

  221. Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y, Harris T, et al. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 2009;15(2):114–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442(7101):461–5.

    Article  CAS  PubMed  Google Scholar 

  223. Wang YQ, Ugai S, Shimozato O, Yu L, Kawamura K, Yamamoto H, et al. Induction of systemic immunity by expression of interleukin-23 in murine colon carcinoma cells. Int J Cancer. 2003;105(6):820–4.

    Article  CAS  PubMed  Google Scholar 

  224. Shimozato O, Ugai S, Chiyo M, Takenobu H, Nagakawa H, Wada A, et al. The secreted form of the p40 subunit of interleukin (IL)-12 inhibits IL-23 functions and abrogates IL-23-mediated antitumour effects. Immunology. 2006;117(1):22–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Shan BE, Hao JS, Li QX, Tagawa M. Antitumor activity and immune enhancement of murine interleukin-23 expressed in murine colon carcinoma cells. Cell Mol Immunol. 2006;3(1):47–52.

    CAS  PubMed  Google Scholar 

  226. Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW, et al. Antitumor and antimetastatic activity of IL-23. J Immunol. 2003;171(2):600–7.

    Article  CAS  PubMed  Google Scholar 

  227. Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010;11(12):1093–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. McNamee EN, Masterson JC, Jedlicka P, McManus M, Grenz A, Collins CB, et al. Interleukin 37 expression protects mice from colitis. Proc Natl Acad Sci U S A. 2011;108(40):16711–6.

    Article  PubMed  PubMed Central  Google Scholar 

  229. Bulau AM, Fink M, Maucksch C, Kappler R, Mayr D, Wagner K, et al. In vivo expression of interleukin-37 reduces local and systemic inflammation in concanavalin A-induced hepatitis. ScientificWorldJournal. 2011;11:2480–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Wirtz S, Billmeier U, McHedlidze T, Blumberg RS, Neurath MF. Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology. 2011;141(5):1875–86.

    Article  CAS  PubMed  Google Scholar 

  231. Kochetkova I, Golden S, Holderness K, Callis G, Pascual DW. IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol. 2010;184(12):7144–53.

    Article  CAS  PubMed  Google Scholar 

  232. Chaturvedi V, Collison LW, Guy CS, Workman CJ, Vignali DA. Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol. 2011;186(12):6661–6.

    Article  CAS  PubMed  Google Scholar 

  233. Niedobitek G, Pazolt D, Teichmann M, Devergne O. Frequent expression of the Epstein-Barr virus (EBV)-induced gene, EBI3, an IL-12 p40-related cytokine, in Hodgkin and Reed-Sternberg cells. J Pathol. 2002;198(3):310–6.

    Article  CAS  PubMed  Google Scholar 

  234. Poleganov MA, Bachmann M, Pfeilschifter J, Muhl H. Genome-wide analysis displays marked induction of EBI3/IL-27B in IL-18-activated AML-derived KG1 cells: critical role of two kappaB binding sites in the human EBI3 promotor. Mol Immunol. 2008;45(10):2869–80.

    Article  CAS  PubMed  Google Scholar 

  235. Nishino R, Takano A, Oshita H, Ishikawa N, Akiyama H, Ito H, et al. Identification of Epstein-Barr virus-induced gene 3 as a novel serum and tissue biomarker and a therapeutic target for lung cancer. Clin Cancer Res. 2011;17(19):6272–86.

    Article  CAS  PubMed  Google Scholar 

  236. Olson BM, Jankowska-Gan E, Becker JT, Vignali DA, Burlingham WJ, McNeel DG. Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade. J Immunol. 2012;189(12):5590–601.

    Article  CAS  PubMed  Google Scholar 

  237. Wang Z, Liu JQ, Liu Z, Shen R, Zhang G, Xu J, et al. Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis. J Immunol. 2013;190(5):2415–23.

    Article  CAS  PubMed  Google Scholar 

  238. Turnis ME, Sawant DV, Szymczak-Workman AL, Andrews LP, Delgoffe GM, Yano H, et al. Interleukin-35 limits anti-tumor immunity. Immunity. 2016;44(2):316–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM, O’Garra A. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity. 2009;31(2):209–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res. 2011;51(2-3):170–82.

    Article  CAS  PubMed  Google Scholar 

  241. Galizia G, Orditura M, Romano C, Lieto E, Castellano P, Pelosio L, et al. Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. Clin Immunol. 2002;102(2):169–78.

    Article  CAS  PubMed  Google Scholar 

  242. Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity. 2008;28(4):468–76.

    Article  CAS  PubMed  Google Scholar 

  243. Seo N, Hayakawa S, Tokura Y. Mechanisms of immune privilege for tumor cells by regulatory cytokines produced by innate and acquired immune cells. Semin Cancer Biol. 2002;12(4):291–300.

    Article  CAS  PubMed  Google Scholar 

  244. Huang S, Ullrich SE, Bar-Eli M. Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. J Interferon Cytokine Res. 1999;19(7):697–703.

    Article  CAS  PubMed  Google Scholar 

  245. Kurte M, Lopez M, Aguirre A, Escobar A, Aguillon JC, Charo J, et al. A synthetic peptide homologous to functional domain of human IL-10 down-regulates expression of MHC class I and transporter associated with antigen processing 1/2 in human melanoma cells. J Immunol. 2004;173(3):1731–7.

    Article  CAS  PubMed  Google Scholar 

  246. Mocellin S, Marincola FM, Young HA. Interleukin-10 and the immune response against cancer: a counterpoint. J Leukoc Biol. 2005;78(5):1043–51.

    Article  CAS  PubMed  Google Scholar 

  247. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006;212:28–50.

    Article  CAS  PubMed  Google Scholar 

  248. Teng MW, Darcy PK, Smyth MJ. Stable IL-10: a new therapeutic that promotes tumor immunity. Cancer Cell. 2011;20(6):691–3.

    Article  CAS  PubMed  Google Scholar 

  249. Berman RM, Suzuki T, Tahara H, Robbins PD, Narula SK, Lotze MT. Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol. 1996;157(1):231–8.

    CAS  PubMed  Google Scholar 

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Garo, L.P., Gopal, M. (2020). Role of Cytokines in Tumor Immunity and Immune Tolerance to Cancer. In: Rezaei, N. (eds) Cancer Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-30845-2_13

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