Cytokine patterns in patients with cancer: a systematic review.

Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types, but owing to the heterogeneity of cancer theories of common reaction mechanisms seem to be obsolete. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor β (TGFβ), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4). Clinical data were analysed in a non-quantitative descriptive manner and interpreted with regard to experimentally established physiological cytokine interactions. The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFβ. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12-interferon-γ-HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient's prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer.

[1]  K. Grote,et al.  How much is too much? Interleukin-6 and its signalling in atherosclerosis , 2009, Thrombosis and Haemostasis.

[2]  G. Beatty,et al.  Regulation of tumor growth by IFN-γ in cancer immunotherapy , 2001 .

[3]  T. Calandra,et al.  Macrophage migration inhibitory factor: a regulator of innate immunity , 2003, Nature Reviews Immunology.

[4]  G. Prud’homme Pathobiology of transforming growth factor β in cancer, fibrosis and immunologic disease, and therapeutic considerations , 2007, Laboratory Investigation.

[5]  Xiaozhe Han,et al.  Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation. , 2013, Journal of autoimmunity.

[6]  T. Whiteside Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression , 2010, Expert opinion on biological therapy.

[7]  F. Brombacher,et al.  T Helper1/T Helper2 Cells and Resistance/Susceptibility to Leishmania Infection: Is This Paradigm Still Relevant? , 2012, Front. Immun..

[8]  B. Nelson IL-2, Regulatory T Cells, and Tolerance , 2004, The Journal of Immunology.

[9]  K. Mohammad,et al.  Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. , 2007, Cancer research.

[10]  M. Ogawa,et al.  IL-6 and IFN-gamma regulation of IL-10 production by human colon carcinoma cells. , 2001, International journal of oncology.

[11]  Xia Zhang,et al.  Interleukin‐10: new perspectives on an old cytokine , 2008, Immunological reviews.

[12]  E. Kovacs Interleukin-6 leads to interleukin-10 production in several human multiple myeloma cell lines. Does interleukin-10 enhance the proliferation of these cells? , 2010, Leukemia research.

[13]  S. Hollenberg,et al.  Cardiac dysfunction in severe sepsis and septic shock , 2009, Current opinion in critical care.

[14]  A. Cerwenka,et al.  CD28, IL-2-independent costimulatory pathways for CD8 T lymphocyte activation. , 1999, Journal of immunology.

[15]  Beverly A. Teicher,et al.  CXCL12 (SDF-1)/CXCR4 Pathway in Cancer , 2010, Clinical Cancer Research.

[16]  D. Vignali,et al.  How regulatory T cells work , 2008, Nature Reviews Immunology.

[17]  Robert D. Schreiber,et al.  Interferons, immunity and cancer immunoediting , 2006, Nature Reviews Immunology.

[18]  S. Matsuda,et al.  Synergistic Effects of IL-4 and IL-18 on IL-12-Dependent IFN-γ Production by Dendritic Cells1 , 2000, The Journal of Immunology.

[19]  J Wagner,et al.  Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. , 2000, Immunity.

[20]  George Coukos,et al.  T-regulatory cells: key players in tumor immune escape and angiogenesis. , 2012, Cancer research.

[21]  F. Balkwill Tumour necrosis factor and cancer , 2009, Nature Reviews Cancer.

[22]  John David,et al.  Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: Regulatory role in the innate immune response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Mcclanahan,et al.  IL-23 promotes tumour incidence and growth , 2006, Nature.

[24]  S. Donnelly,et al.  Inflammation and cancer: macrophage migration inhibitory factor (MIF)—the potential missing link , 2010, QJM : monthly journal of the Association of Physicians.

[25]  C. Dinarello,et al.  Clinical and experimental approaches to the pathophysiology of interleukin-18 in cancer progression , 2006, Cancer and Metastasis Reviews.

[26]  R. D. Hatton,et al.  Transforming growth factor-β induces development of the TH17 lineage , 2006, Nature.

[27]  Y. Kono,et al.  Effects of IL6 on B cells in mucosal immune response and inflammation. , 1992, Research in immunology.

[28]  Daniel P. Bailey,et al.  Mast cell homeostasis: a fundamental aspect of allergic disease. , 2007, Critical reviews in immunology.

[29]  M. Pfreundschuh,et al.  Serological identification of human tumor antigens. , 1997, Current opinion in immunology.

[30]  C. Drake,et al.  Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. , 2009, Cancer cell.

[31]  M. Katoh,et al.  Integrative genomic analyses of CXCR4: transcriptional regulation of CXCR4 based on TGFbeta, Nodal, Activin signaling and POU5F1, FOXA2, FOXC2, FOXH1, SOX17, and GFI1 transcription factors. , 2009, International journal of oncology.

[32]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[33]  R. Schwartz,et al.  Smad3 Is Essential for TGF-β1 to Suppress IL-2 Production and TCR-Induced Proliferation, but Not IL-2-Induced Proliferation1 , 2004, The Journal of Immunology.

[34]  O. Eremin,et al.  Tumour-associated macrophages (TAMS): disordered function, immune suppression and progressive tumour growth. , 2000, Journal of the Royal College of Surgeons of Edinburgh.

[35]  L. Old,et al.  T-cell-mediated cytotoxicity against autologous malignant melanoma: analysis with interleukin 2-dependent T-cell cultures. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[36]  V. Dixit,et al.  Signaling in innate immunity and inflammation. , 2012, Cold Spring Harbor perspectives in biology.

[37]  P. ten Dijke,et al.  Exploring anti-TGF-β therapies in cancer and fibrosis , 2011, Growth factors.

[38]  C. Esmon Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. , 1994, Bailliere's clinical haematology.

[39]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[40]  C. Bogdan,et al.  The Production of IFN-γ by IL-12/IL-18-Activated Macrophages Requires STAT4 Signaling and Is Inhibited by IL-41 , 2001, The Journal of Immunology.

[41]  M. Gore,et al.  Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[43]  Seong-Jin Kim,et al.  Transforming Growth Factor-β: Biology and Clinical Relevance , 2005 .

[44]  G. Trinchieri Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. , 1995, Annual review of immunology.

[45]  L. Coussens,et al.  Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity , 2010, Cancer and Metastasis Reviews.

[46]  J. Harty,et al.  CD8+ T cell effector mechanisms in resistance to infection. , 2000, Annual review of immunology.

[47]  M. Atkins,et al.  Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  B. Becher,et al.  IL‐23: One cytokine in control of autoimmunity , 2012, European journal of immunology.

[49]  L. Hennighausen,et al.  Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. , 2007, Immunity.

[50]  A. Harris,et al.  A Phase II Study of Etanercept (Enbrel), a Tumor Necrosis Factor α Inhibitor in Patients with Metastatic Breast Cancer , 2004, Clinical Cancer Research.

[51]  G. Ciliberto,et al.  Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. , 1997, Immunity.

[52]  Mario Roederer,et al.  Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients , 1999, Nature Medicine.

[53]  R. Wall,et al.  Beta transforming growth factors are potential regulators of B lymphopoiesis , 1987, The Journal of experimental medicine.

[54]  G. Trinchieri,et al.  The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. , 2003, Immunity.

[55]  Yanping Zhang,et al.  Tumor Microenvironments Direct the Recruitment and Expansion of Human Th17 Cells , 2009, The Journal of Immunology.

[56]  P. Allavena,et al.  Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. , 2002, Trends in immunology.

[57]  A. Ben-Baruch Organ selectivity in metastasis: regulation by chemokines and their receptors , 2007, Clinical & Experimental Metastasis.

[58]  A. Frey,et al.  Effector‐phase tolerance: another mechanism of how cancer escapes antitumor immune response , 2006, Journal of leukocyte biology.

[59]  Thomas Korn,et al.  IL-17 and Th17 Cells. , 2009, Annual review of immunology.

[60]  P. Allavena,et al.  Role of tumor-associated macrophages in tumor progression and invasion , 2006, Cancer and Metastasis Reviews.

[61]  P. Lei,et al.  Transforming growth factor-β1 upregulates the expression of CXC chemokine receptor 4 (CXCR4) in human breast cancer MCF-7 cells , 2010, Acta Pharmacologica Sinica.

[62]  M. Sporn,et al.  Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth , 1986, The Journal of experimental medicine.

[63]  K. Murphy,et al.  The role of macrophage- and dendritic cell-derived IL12 in Th1 phenotype development. , 1995, Research in immunology.

[64]  T. Calandra Macrophage Migration Inhibitory Factor and Host Innate Immune Responses to Microbes , 2003, Scandinavian journal of infectious diseases.

[65]  R. Schreiber,et al.  The immunobiology of cancer immunosurveillance and immunoediting. , 2004, Immunity.

[66]  D. Lebman,et al.  The role of TGF-β in growth, differentiation, and maturation of B lymphocytes , 1999 .

[67]  G. Trinchieri,et al.  Interleukin-12 and the regulation of innate resistance and adaptive immunity , 2003, Nature Reviews Immunology.

[68]  J. McPherson,et al.  Antibody targeting of TGF-β in cancer patients. , 2011, Current pharmaceutical biotechnology.

[69]  Michael Bacher,et al.  Macrophage migration inhibitory factor: Roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma , 2003, International journal of cancer.

[70]  J. Herbeuval,et al.  Recruitment of STAT3 for Production of IL-10 by Colon Carcinoma Cells Induced by Macrophage-Derived IL-61 , 2004, The Journal of Immunology.

[71]  A. Mantovani,et al.  Cytokines as communication signals between leukocytes and endothelial cells. , 1989, Immunology today.

[72]  C. Roussos,et al.  Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion , 2007 .

[73]  J. Bernhagen,et al.  MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment , 2007, Nature Medicine.

[74]  A. Mantovani,et al.  IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. , 2003, Trends in immunology.

[75]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[76]  S. Wojtowicz-Praga Reversal of Tumor-Induced Immunosuppression: A New Approach to Cancer Therapy , 1997, Journal of immunotherapy.

[77]  A. Abbas,et al.  Cellular and Molecular Immunology , 1991 .

[78]  Beverly A. Teicher,et al.  Transforming Growth Factor-β and the Immune Response to Malignant Disease , 2007, Clinical Cancer Research.

[79]  A. Zlotnik New insights on the role of CXCR4 in cancer metastasis , 2008, The Journal of pathology.

[80]  M. Karin,et al.  Immunity, Inflammation, and Cancer , 2010, Cell.

[81]  F. Marincola,et al.  Interleukin‐10 and the immune response against cancer: a counterpoint , 2005, Journal of leukocyte biology.

[82]  K. Schlingensiepen,et al.  The antisense oligonucleotide trabedersen (AP 12009) for the targeted inhibition of TGF-β2. , 2011, Current pharmaceutical biotechnology.

[83]  P. Chomez,et al.  A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. , 1991, Science.

[84]  G. Trinchieri Cancer and inflammation: an old intuition with rapidly evolving new concepts. , 2012, Annual review of immunology.