Ovarian cancer is the most common malignant disease leading to death among women. IL (interleukin)-17A is the most well-studied member of the IL-17 family, and has been demonstrated to play a critical role in host defenses against various microbial pathogens, as well as against tissue inflammation. T-helper (Th)17 cells that produce interleukin (IL)-17A are of particular importance, because IL-17A exerts a wide variety of biological functions, particularly related to inflammation and the resultant carcinoge nesis, as well as immune suppression in patients with cancer, and IL-17A-targeted therapy has been proven to be effective in the treatment of some autoimmune diseases. The pathogenic features of Th17 and IL-17A cells in cancer are still controversial, and Th17 cells appear to promote disease progression, as well as be present in the vicinity of many types of malignant diseases. In cancer patients, MDSC (myeloid-derived suppressor cells), one of the major immunosuppressive immature cells, and VEGF (vascular endothelial growth factor) are reported to correlate each other and strongly connected to IL-17-driven inflammation and malnutrition. In the present review, the latest advances are presented about the basic features of IL-17A and Th17. The function of IL-17A has not been clarified especially in ovarian cancer. This review overview the basic features of IL-17A and the functions in ovarian cancer as well as in other malignant and non-malignant diseases. Increasing our understanding of the interactions between IL-17A and ovarian cancer could lead to new therapeutic strategies in oncology.
American Cancer Society (2017) Cancer Facts and Figures. Genes & Development, 21, 2525-2538. https://doi.org/10.1101/gad.1593107
Rizzuto, I., Stavraka, C., Chatterjee, J., et al. (2015) Risk of Ovarian Cancer Relapse Score: A Prognostic Algorithm to Predict Relapse Following Treatment for Advanced Ovarian Cancer. International Journal of Gynecologic Cancer, 25, 416-422. https://doi.org/10.1097/IGC.0000000000000361
Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Cancer: The Next Generation. Cell, 144, 646-674. https://doi.org/10.1016/j.cell.2011.02.013
Bindea, G., Mlecnik, B., Tosolini, M., et al. (2013) Spatiotemporal Dynamics of Intratumoral Immune Cells Reveal the Immune Landscape in Human Cancer. Immunity, 39, 782-795. https://doi.org/10.1016/j.immuni.2013.10.003
Chen, K. and Kolls, J.K. (2017) Interleukin-17A (IL-17A). Gene, 614, 8-14. https://doi.org/10.1016/j.gene.2017.01.016
Fossiez, F., Djossou, O., Chomarat, P., et al. (1996) T Cell Interleukin-17 Induces Stromal Cells to Produce Proinflammatory and Hematopoietic Cytokines. Journal of Experimental Medicine, 183, 2593-2603. https://doi.org/10.1084/jem.183.6.2593
Harrington, L.E., Hatton, R.D., Mangan, P.R., et al. (2005) Interleukin-17-Producing CD4+ Effector T Cells Develop via a Lineage Distinct from the T Helper Type 1 and 2 Lineages. Nature Immunology, 6, 1123-1132. https://doi.org/10.1038/ni1254
Mathur, A.N., Chang, H.C., Zisoulis, D.G., et al. (2017) Stat3 and Stat4 Direct Development of IL-17-Secreting Th Cells. Journal of Immunology, 178, 4901-4907. https://doi.org/10.4049/jimmunol.178.8.4901
Ivanov II McKenzie, B.S., Zhou, L., Tadokoro, C.E., et al. (2006) The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells. Cell, 126, 1121-1133. https://doi.org/10.1016/j.cell.2006.07.035
Yao, Z., Fanslow, W.C., Seldin, M.F., et al. (1995) Herpesvirus Saimiri Encodes a New Cytokine, IL-17, Which Binds to a Novel Cytokine Receptor. Immunity, 3, 811-821. https://doi.org/10.1016/1074-7613(95)90070-5
Gaffen, S.L. (2009) Structure and Signaling in the IL-17 Receptor Family. Nature Review of Immunology, 9, 556-567. https://doi.org/10.1038/nri2586
Cua, D.J. and Tato, C.M. (2010) Innate IL-17-Producing Cells: The Sentinels of the Immune System. Nature Review of Immunology, 10, 479-489. https://doi.org/10.1038/nri2800
Shabgah, A.G., Fattahi, E. and Shahneh, F.Z. (2014) Interleukin-17 in Human Inflammatory Diseases. Advances in Dermatology and Allergology, 31, 256-261. https://doi.org/10.5114/pdia.2014.40954
Rankin, L.C., Girard-Madoux, M.J., Seillet, C., et al. (2016) Complementarity and Redundancy of IL-22-Producing Innate Lymphoid Cells. Nature Immunology, 17, 179-186. https://doi.org/10.1038/ni.3332
Takahashi, N., Vanlaere, I., de Rycke, R., et al. (2008) IL-17 Produced by Paneth Cells Drives TNF-Induced Shock. Journal of Experimental Medicine, 205, 1755-1761. https://doi.org/10.1084/jem.20080588
Kumar, P., Monin, L., Castillo, P., et al. (2016) Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation. Immunity, 44, 659-671. https://doi.org/10.1016/j.immuni.2016.02.007
Crowe, C.R., Chen, K., Pociask, D.A., et al. (2009) Critical Role of IL-17RA in Immunopathology of Influenza Infection. Journal of Immunology, 183, 5301-5310. https://doi.org/10.4049/jimmunol.0900995
Sears, C.L. and Garett, W.S. (2014) Microbes, Microbiota, and Colon Cancer. Cell Host and Microbe, 15, 317-328. https://doi.org/10.1016/j.chom.2014.02.007
Wang, K., Kim, M.K., Di Carlo, G., et al. (2014) Interleukin 17 Receptor Signaling in Transformed Enterocytes Promotes Early Colorectal Tumorigenesis. Immunity, 41, 1052-1063. https://doi.org/10.1016/j.immuni.2014.11.009
Bagheri, N., Azadegan-Dehkordi, F., Shirzad, H., et al. (2015) The Biological Functions of IL-17 in Different Clinical Expressions of Helicobacter pylori-Infection. Microbial Pathogenesis, 81, 33-38. https://doi.org/10.1016/j.micpath.2015.03.010
Atarashi, K., Tanoue, T., Ando, M., et al. (2015) Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells. Cell, 163, 367-380. https://doi.org/10.1016/j.cell.2015.08.058
Korn, T., Bettelli, E., Oukka, M. and Kuchroo, V.K. (2009) IL-17 and Th17 Cells. Annual Review of Immunology, 27, 485-517. https://doi.org/10.1146/annurev.immunol.021908.132710
Park, H., Li, Z., Yang, X.O., et al. (2005) A Distinct Lineage of CD4 T Cells Regulates Tissue Inflammation by Producing Interleukin 17. Nature Immunology, 6, 1133-1141. https://doi.org/10.1038/ni1261
Matusevicius, D., Kivisakk, P., He, B., et al. (1999) Interleukin-17 mRNA Expression in Blood and CSF Mononuclear Cells Is Augmented in Multiple Sclerosis. Multiple Sclerosis, 5, 101-104. https://doi.org/10.1177/135245859900500206
Lowes, M.A., Bowcock, A.M. and Krueger, J.G. (2007) Pathogenesis and Therapy of Psoriasis. Nature, 445, 866-873. https://doi.org/10.1038/nature05663
Di Cesare, A., Di Meglio, P. and Nestle, F.O. (2009) The IL-23/Th17 Axis in the Immunopathogenesis of Psoriasis. Journal of Investigative Dermatology, 129, 1339-1350. https://doi.org/10.1038/jid.2009.59
Kirkham, B.W., Lassere, M.N., Edmonds, J.P., et al. (2006) Synovial Membrane Cytokine Expression Is Predictive of Joint Damage Progression in Rheumatoid Arthritis: A Two-Year Prospective Study (the DAMAGE Study Cohort). Arthritis and Rheumatology, 54, 1121-1131. https://doi.org/10.1002/art.21749
Genovese, M.C., Durez, P., Richards, H.B., et al. (2014) One-Year Efficacy and Safety Results of Secukinumab in Patients with Rheumatoid Arthritis: Phase II, Dose-Finding, Double Blind, Randomized, Placebo-Controlled Study. Journal of Rheumatology, 41, 414-421. https://doi.org/10.3899/jrheum.130637
Monteleone, I., Sarra, M., Pallone, F. and Monteleone, G. (2012) Th17-Related Cytokines in Inflammatory Bowel Diseases: Friends or Foes? Current Molecular Medicine, 12, 592-597. https://doi.org/10.2174/156652412800620066
Hueber, W., Sands, B.E., Lewitzky, S., et al. (2012) Secukinumab, a Human Anti-IL-17A Monoclonal Antibody, for Moderate to Severe Crohn’s Disease: Unexpected Results of a Randomised, Double-Blind Placebo Controlled Trial. Gut, 61, 1693-1700. https://doi.org/10.1136/gutjnl-2011-301668
Zhao, F., Hoechst, B., Gamrekelashvili, J., et al. (2008) Human CCR4+CCR6+Th17 Cells Suppress Autologous CD8+T Cell Responses. Journal of Immunology, 188, 6055-6062. https://doi.org/10.4049/jimmunol.1102918
Mantovani, A., Allavena, P., Sica, A. and Balkwill, F. (2008) Cancer-Related Inflammation. Nature, 454, 436-444. https://doi.org/10.1038/nature07205
Pasquier, J. and Rafii, A. (2013) Role of the Microenvironment in Ovarian Cancer Stem Cell Maintenance. BioMed Research International, 2013, Article ID: 630782. https://doi.org/10.1155/2013/630782
Xiang, T., Long, H., He, L., et al. (2015) Interleukin-17 Produced by Tumor Microenvironment Promotes Self-Renewal of CD133+ Cancer Stem-Like Cells in Ovarian Cancer. Oncogene, 34, 165-176. https://doi.org/10.1038/onc.2013.537
Yamada, Y., Saito, H. and Ikeguchi, M. (2012) Prevalence and Clinical Relevance of Th17 in Patients with Gastric Cancer. Journal of Surgical Research, 178, 685-691. https://doi.org/10.1016/j.jss.2012.07.055
Miyahara, Y., Odunsi, K., Chen, W., et al. (2008) Generation and Regulation of Human CD4+IL-17 Producing T Cells in Ovarian Cancer. Proceedings of the National Academy of Science of USA, 105, 15505-15510. https://doi.org/10.1073/pnas.0710686105
Maruyama, T., Kono, K., Mizukami, Y., et al. (2010) Distribution of Th17 Cells and FoxP3(+) Regulatory T Cells in Tumor-Infiltrating Lymphocytes, Tumor-Draining Lymph Nodes and Peripheral Blood Lymphocytes in Patients with Gastric Cancer. Cancer Science, 101, 1947-1954. https://doi.org/10.1111/j.1349-7006.2010.01624.x
Tosolini, M., Kirilovsky, A., Mlecnik, B., et al. (2011) Clinical Impact of Different Classes of Infiltrating T Cytotoxic and Helper Cells (Th1, th2, treg, th17) in Patients with Colorectal Cancer. Cancer Research, 71, 1263-1271. https://doi.org/10.1158/0008-5472.CAN-10-2907
He, S., Fei, M., Wu, Y., et al. (2011) Distribution and Clinical Significance of Th17 Cells in the Tumor Microenvironment and Peripheral Blood of Pancreatic Cancer Patients. International Journal of Molecular Sciences, 12, 7424-7437. https://doi.org/10.3390/ijms12117424
Su, X., Ye, J., Hsueh, E.C., et al. (2010) Tumor Microenvironments Direct the Recruitment and Expansion of Human Th17 Cells. The Journal of Immunology, 184, 1630-1641. https://doi.org/10.4049/jimmunol.0902813
Wang, L., Yi, T., Kortylewski, M., et al. (2009) IL-17 Can Promote Tumor Growth through an IL-6-Stat3 Signaling Pathway. Journal of Experimental Medicine, 206, 1457-1464. https://doi.org/10.1084/jem.20090207
Liu, J., Duan, Y., Cheng, X., et al. (2011) IL-17 Is Associated with Poor Prognosis and Promotes Angiogenesis via Stimulating VEGF Production of Cancer Cells in Colorectal Carcinoma. Biochemical and Biophysical Research Communications, 407, 348-354. https://doi.org/10.1016/j.bbrc.2011.03.021
Talmadge, J.E. and Gabrilovich, D.I. (2013) History of Myeloid-Derived Suppressor Cells. Nature Reviews Cancer, 13, 739-752. https://doi.org/10.1038/nrc3581
Zea, A.H., Rodriguez, P.C., Atkins, M.B., et al. (2005) Arginase-Producing Myeloid Suppressor Cells in Renal Cell Carcinoma Patients. Cancer Research, 65, 3044-3048. https://doi.org/10.1158/0008-5472.CAN-04-4505
Ochoa, A.C., Zea, A.H., Hernandez, C. and Rodriguez, P.C. (2007) Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma. Clinical Cancer Research, 13, 721s-726s. https://doi.org/10.1158/1078-0432.CCR-06-2197
Diaz-Montero, C.M., Salem, M.L., Nishimura, M.I., et al. (2009) Increased Circulating Myeloid-Derived Suppressor Cells Correlate with Clinical Cancer Stage, Metastatic Tumor Burden, and Doxorubicin-Cyclophosphamide Chemotherapy. Cancer Immunology and Immunotherapy, 58, 49-59. https://doi.org/10.1007/s00262-008-0523-4
Gabrilovich, D.I. and Nagaraj, S. (2009) Myeloid-Derived Suppressor Cells as Regulators of the Immune System. Nature Reviews Immunology, 9, 162-174. https://doi.org/10.1038/nri2506
Ostrand-Rosenberg, S. and Sinha, P. (2009) Myeloid-Derived Suppressor Cells: Linking Inflammation and Cancer. Journal of Immunology, 182, 4499-4506. https://doi.org/10.4049/jimmunol.0802740
Suzuki, S., Shibata, M., Gonda, K., et al. (2013) Immunosuppression Involving Increased Myeloid-Derived Suppressor Cell Levels, Systemic Inflammation, and Hypoalbuminemia Are Present in Patients with Anaplastic Thyroid Cancer. Molecular and Clinical Oncology, 1, 959-964. https://doi.org/10.3892/mco.2013.170
Yazawa, T., Shibata, M., Gonda, K., et al. (2013) Increased IL-17 Production Correlated with Immunosuppression Involving Myeloid-Derived Suppressor Cells and Nutritional Impairment in Patients with Various Gastrointestinal Cancers. Molecular and Clinical Oncology, 1, 675-679. https://doi.org/10.3892/mco.2013.134
Ohki, S., Shibata, M., Gonda, K., et al. (2012) Circulating Myeloid-Derived Suppressor Cells Are Increased and Correlate to Immune Suppression, Inflammation and Hypoproteinemia in Patients with Cancer. Oncology Reports, 28, 453-458. https://doi.org/10.3892/or.2012.1812
Tachibana, K., Shibata, M., Gonda, K., et al. (2017) IL-17 and VEGF Are Increased and Correlated to Systemic Inflammation, Immune Suppression, and Malnutrition in Patients with Breast Cancer. European Journal of Inflammation, 20, 1-10. https://doi.org/10.1177/1721727X17739514
Minamikawa, K., Shibata, M., Gonda, K., et al. (2017) IL-17 and VEGF Are Significantly Associated with Disease Progression Involving Systemic Inflammation in Patients with Gastric and Colorectal Cancers. Annals Cancer Research and Therapy, 25, 67-76. https://doi.org/10.4993/acrt.25.67
Aotsuka, A., Matsumoto, Y., Arimoto, T., et al. (2019) Interleukin-17 Is Associated with Expression of Programmed Cell Death 1 Ligand 1 in Ovarian Carcinoma. Cancer Science, 110, 3068-3078. https://doi.org/10.1111/cas.14174
Lan, C., Huang, X., Lin, S., et al. (2013) High Density of IL-17 Producing Cells Is Associated with Improved Prognosis for Advanced Epithelial Ovarian Cancer. Cell and Tissue Research, 352, 351-359. https://doi.org/10.1007/s00441-013-1567-0
Droeser, R.A., Mechera, R., Daster, S., et al. (2016) MPO Density in Primary Cancer Biopsies of Ovarian Carcinoma Enhances the Indicative Value of IL-17 for Chemosensitivity. BMC Cancer, 16, 639. https://doi.org/10.1186/s12885-016-2673-7
Rungapiromnan, W., Yiu, Z.Z.N., Warren, R.B., et al. (2017) Impact of Biologic Therapies on Risk of Major Adverse Cardiovascular Events in Patients with Psoriasis: Systematic Review and Meta-Analysis of Randomized Controlled Trials. British Journal of Dermatology, 176, 890-901. https://doi.org/10.1111/bjd.14964
Huh, J.R. and Littman, D.R. (2012) Small Molecule Inhibitors of RORγt: Targeting Th17 Cells and Other Applications. European Journal of Immunology, 42, 2232-2237. https://doi.org/10.1002/eji.201242740