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RETRACTED ARTICLE: Targeted immune therapy of ovarian cancer

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Cancer and Metastasis Reviews Aims and scope Submit manuscript

This article was retracted on 30 May 2016

Abstract

Clinical outcomes, such as recurrence-free survival and overall survival, in ovarian cancer are quite variable, independent of common characteristics such as stage, response to therapy, and grade. This disparity in outcomes warrants further exploration and therapeutic targeting into the interaction between the tumor and host. One compelling host characteristic that contributes both to the initiation and progression of ovarian cancer is the immune system. Hundreds of studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease. Recent studies also show that anti-tumor immunity is often negated by immune regulatory cells present in the tumor microenvironment. Regulatory immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathological network. Thus, in the future, research into immunotherapy targeting ovarian cancer will probably become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression. In this article, we summarize important immunological targets that influence ovarian cancer outcome as well as include an update on newer immunotherapeutic strategies.

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References

  1. Siegel, R., Naishadham, D., & Jemal, A. (2013). Cancer statistics, 2013. A Cancer Journal for Clinicians, 63(1), 11–30. doi:10.3322/caac.21166.

    Article  Google Scholar 

  2. Aletti, G. D., Gallenberg, M. M., Cliby, W. A., Jatoi, A., & Hartmann, L. C. (2007). Current management strategies for ovarian cancer. Mayo Clinic Proceedings, 82(6), 751–770. doi:10.4065/82.6.751.

    Article  PubMed  Google Scholar 

  3. Cannistra, S. A. (2004). Cancer of the ovary. The New England Journal of Medicine, 351(24), 2519–2529. doi:10.1056/NEJMra041842.

    Article  CAS  PubMed  Google Scholar 

  4. Ozols, R. F., Bundy, B. N., Greer, B. E., Fowler, J. M., Clarke-Pearson, D., Burger, R. A., et al. (2003). Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A gynecologic oncology group study. Journal of Clinical Oncology, 21(17), 3194–3200. doi:10.1200/JCO.2003.02.153.

    Article  CAS  PubMed  Google Scholar 

  5. Vaughan, S., Coward, J. I., Bast, R. C., Jr., Berchuck, A., Berek, J. S., Brenton, J. D., et al. (2011). Rethinking ovarian cancer: Recommendations for improving outcomes. Nature Reviews Cancer, 11(10), 719–725. doi:10.1038/nrc3144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Merritt, M. A., Green, A. C., Nagle, C. M., Webb, P. M., & S. Australian Cancer, and G. Australian Ovarian Cancer Study. (2008). Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer. International Journal of Cancer, 122(1), 170–176. doi:10.1002/ijc.23017.

    Article  CAS  PubMed  Google Scholar 

  7. Mahdavi, A., Pejovic, T., & Nezhat, F. (2006). Induction of ovulation and ovarian cancer: A critical review of the literature. Fertility and Sterility, 85(4), 819–826. doi:10.1016/j.fertnstert.2005.08.061.

    Article  CAS  PubMed  Google Scholar 

  8. Adami, H. O., Hsieh, C. C., Lambe, M., Trichopoulos, D., Leon, D., Persson, I., et al. (1994). Parity, age at first childbirth, and risk of ovarian cancer. Lancet, 344(8932), 1250–1254.

    Article  CAS  PubMed  Google Scholar 

  9. Modan, B., Hartge, P., Hirsh-Yechezkel, G., Chetrit, A., Lubin, F., Beller, U., et al. (2001). Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. The New England Journal of Medicine, 345(4), 235–240. doi:10.1056/NEJM200107263450401.

    Article  CAS  PubMed  Google Scholar 

  10. Collaborative Group on Epidemiological Studies of Ovarian, C, Beral, V., Doll, R., Hermon, C., Peto, R., & Reeves, G. (2008). Ovarian cancer and oral contraceptives: Collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet, 371(9609), 303–314. doi:10.1016/S0140-6736(08)60167-1.

    Article  CAS  Google Scholar 

  11. Narod, S. A., Risch, H., Moslehi, R., Dorum, A., Neuhausen, S., Olsson, H., et al. (1998). Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary ovarian cancer clinical study group. The New England Journal of Medicine, 339(7), 424–428. doi:10.1056/NEJM199808133390702.

    Article  CAS  PubMed  Google Scholar 

  12. Jordan, S. J., Cushing-Haugen, K. L., Wicklund, K. G., Doherty, J. A., & Rossing, M. A. (2012). Breast-feeding and risk of epithelial ovarian cancer. Cancer Causes & Control, 23(6), 919–927. doi:10.1007/s10552-012-9963-4.

    Article  CAS  Google Scholar 

  13. Jordan, S. J., Siskind, V., C.Green, A., Whiteman, D. C., & Webb, P. M. (2010). Breastfeeding and risk of epithelial ovarian cancer. Cancer Causes & Control, 21(1), 109–116. doi:10.1007/s10552-009-9440-x.

    Article  Google Scholar 

  14. Titus-Ernstoff, L., Perez, K., Cramer, D. W., Harlow, B. L., Baron, J. A., & Greenberg, E. R. (2001). Menstrual and reproductive factors in relation to ovarian cancer risk. British Journal of Cancer, 84(5), 714–721. doi:10.1054/bjoc.2000.1596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Casagrande, J. T., Louie, E. W., Pike, M. C., Roy, S., Ross, R. K., & Henderson, B. E. (1979). “Incessant ovulation” and ovarian cancer. Lancet, 2(8135), 170–173. doi:10.1016/S0140-6736(79)91435-1.

    Article  CAS  PubMed  Google Scholar 

  16. King, S. M., Hilliard, T. S., Wu, L. Y., Jaffe, R. C., Fazleabas, A. T., & Burdette, J. E. (2011). The impact of ovulation on fallopian tube epithelial cells: Evaluating three hypotheses connecting ovulation and serous ovarian cancer. Endocrine Related Cancer, 18(5), 627–642. doi:10.1530/ERC-11-0107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wehner, A. P. (1994). Biological effects of cosmetic talc. Food and Chemical Toxicology, 32(12), 1173–1184.

    Article  CAS  PubMed  Google Scholar 

  18. Mills, P. K., Riordan, D. G., Cress, R. D., & Young, H. A. (2004). Perineal talc exposure and epithelial ovarian cancer risk in the Central Valley of California. International Journal of Cancer, 112(3), 458–464. doi:10.1002/ijc.20434.

    Article  CAS  PubMed  Google Scholar 

  19. Rosenblatt, K. A., Weiss, N. S., Cushing-Haugen, K. L., Wicklund, K. G., & Rossing, M. A. (2011). Genital powder exposure and the risk of epithelial ovarian cancer. Cancer Causes & Control, 22(5), 737–742. doi:10.1007/s10552-011-9746-3.

    Article  Google Scholar 

  20. Wu, A. H., Pearce, C. L., Tseng, C. C., Templeman, C., & Pike, M. C. (2009). Markers of inflammation and risk of ovarian cancer in Los Angeles County. International Journal of Cancer, 124(6), 1409–1415. doi:10.1002/ijc.24091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huncharek, M., Geschwind, J. F., & Kupelnick, B. (2003). Perineal application of cosmetic talc and risk of invasive epithelial ovarian cancer: A meta-analysis of 11,933 subjects from sixteen observational studies. Anticancer Research, 23(2C), 1955–1960.

    PubMed  Google Scholar 

  22. Huncharek, M., & Muscat, J. (2011). Perineal talc use and ovarian cancer risk: A case study of scientific standards in environmental epidemiology. European Journal of Cancer Prevention, 20(6), 501–507. doi:10.1097/CEJ.0b013e3283476242.

    Article  PubMed  Google Scholar 

  23. Pearce, C. L., Templeman, C., Rossing, M. A., Lee, A., Near, A. M., Webb, P. M., et al. (2012). Association between endometriosis and risk of histological subtypes of ovarian cancer: A pooled analysis of case–control studies. The Lancet Oncology, 13(4), 385–394. doi:10.1016/S1470-2045(11)70404-1.

    Article  PubMed  PubMed Central  Google Scholar 

  24. D’Hooghe, T. M., & Debrock, S. (2002). Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Human Reproduction Update, 8(1), 84–88.

    Article  PubMed  Google Scholar 

  25. Risch, H. A., & Howe, G. R. (1995). Pelvic inflammatory disease and the risk of epithelial ovarian cancer. Cancer Epidemiology, Biomarkers & Prevention, 4(5), 447–451.

    CAS  Google Scholar 

  26. Lin, H. W., Tu, Y. Y., Lin, S. Y., Su, W. J., Lin, W. L., Lin, W. Z., et al. (2011). Risk of ovarian cancer in women with pelvic inflammatory disease: A population-based study. The Lancet Oncology, 12(9), 900–904. doi:10.1016/S1470-2045(11)70165-6.

    Article  PubMed  Google Scholar 

  27. Bonovas, S., Filioussi, K., & Sitaras, N. M. (2005). Do nonsteroidal anti-inflammatory drugs affect the risk of developing ovarian cancer? A meta-analysis. British Journal of Clinical Pharmacology, 60(2), 194–203. doi:10.1111/j.1365-2125.2005.02386.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, Z., & Moult, J. (2001). SNPs, protein structure, and disease. Human Mutation, 17(4), 263–270. doi:10.1002/humu.22.

    Article  PubMed  Google Scholar 

  29. Bolton, K. L., Tyrer, J., Song, H., Ramus, S. J., Notaridou, M., Jones, C., et al. (2010). Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nature Genetics, 42(10), 880–884. doi:10.1038/ng.666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Goode, E. L., Chenevix-Trench, G., Song, H., Ramus, S. J., Notaridou, M., Lawrenson, K., et al. (2010). A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nature Genetics, 42(10), 874–879. doi:10.1038/ng.668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Song, H., Ramus, S. J., Tyrer, J., Bolton, K. L., Gentry-Maharaj, A., Wozniak, E., et al. (2009). A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nature Genetics, 41(9), 996–1000. doi:10.1038/ng.424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fan, Y., Yu, W., Ye, P., Wang, H., Wang, Z., Meng, Q., et al. (2011). NFKB1 insertion/deletion promoter polymorphism increases the risk of advanced ovarian cancer in a Chinese population. DNA and Cell Biology, 30(4), 241–245. doi:10.1089/dna.20doi:10.1107.

    Article  CAS  PubMed  Google Scholar 

  33. Lubinski, J., Huzarski, T., Kurzawski, G., Suchy, J., Masojc, B., Mierzejewski, M., et al. (2005). The 3020insC allele of NOD2 predisposes to cancers of multiple organs. Hereditary Cancer in Clinical Practice, 3(2), 59–63. doi:10.1186/1897-4287-3-2-59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. White, K. L., Vierkant, R. A., Phelan, C. M., Fridley, B. L., Anderson, S., Knutson, K. L., et al. (2009). Polymorphisms in NF-kappaB inhibitors and risk of epithelial ovarian cancer. BMC Cancer, 9, 170. doi:10.1186/1471-2407-9-170.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Ma, X., Zhang, J., Liu, S., Huang, Y., Chen, B., & Wang, D. (2011). Polymorphisms in the CASP8 gene and the risk of epithelial ovarian cancer. Gynecologic Oncology, 122(3), 554–559. doi:10.1016/j.ygyno.2011.05.031.

    Article  CAS  PubMed  Google Scholar 

  36. Engel, C., Versmold, B., Wappenschmidt, B., Simard, J., Easton, D. F., Peock, S., et al. (2010). Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiology, Biomarkers & Prevention, 19(11), 2859–2868. doi:10.1158/1055-9965.EPI-10-0517.

    Article  CAS  Google Scholar 

  37. Nevadunsky, N. S., Korneeva, I., Caputo, T., & Witkin, S. S. (2012). Mannose-binding lectin codon 54 genetic polymorphism and vaginal protein levels in women with gynecologic malignancies. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 163(2), 216–218. doi:10.1016/j.ejogrb.2012.04.020.

    Article  CAS  PubMed  Google Scholar 

  38. Lurie, G., Terry, K. L., Wilkens, L. R., Thompson, P. J., McDuffie, K. E., Carney, M. E., et al. (2010). Pooled analysis of the association of PTGS2 rs5275 polymorphism and NSAID use with invasive ovarian carcinoma risk. Cancer Causes & Control, 21(10), 1731–1741. doi:10.1007/s10552-010-9602-x.

    Article  Google Scholar 

  39. White, K. L., Schildkraut, J. M., Palmieri, R. T., Iversen, E. S., Jr., Berchuck, A., Vierkant, R. A., et al. (2012). Ovarian cancer risk associated with inherited inflammation-related variants. Cancer Research, 72(5), 1064–1069. doi:10.1158/0008-5472.CAN-11-3512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liang, D., Meyer, L., Chang, D. W., Lin, J., Pu, X., Ye, Y., et al. (2010). Genetic variants in microRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response. Cancer Research, 70(23), 9765–9776. doi:10.1158/0008-5472.CAN-10-0130.

    Article  CAS  PubMed  Google Scholar 

  41. Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., et al. (2014). Risk of ovarian cancer and the NF-kappaB pathway: Genetic association with IL1A and TNFSF. Cancer Research, 74(3), 852–861. doi:10.1158/0008-5472.CAN-13-1051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Palmieri, R. T., Wilson, M. A., Iversen, E. S., Clyde, M. A., Calingaert, B., Moorman, P. G., et al. (2008). Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women. Cancer Epidemiology, Biomarkers & Prevention, 17(12), 3567–3572. doi:10.1158/1055-9965.EPI-08-0548.

    Article  CAS  Google Scholar 

  43. Gabay, C., & Kushner, I. (1999). Acute-phase proteins and other systemic responses to inflammation. The New England Journal of Medicine, 340(6), 448–454. doi:10.1056/NEJM199902113400607.

    Article  CAS  PubMed  Google Scholar 

  44. Ridker, P. M. (2007). Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: Implications for longevity. Nutrition Reviews, 65(12 Pt 2), S253–S259.

    Article  PubMed  Google Scholar 

  45. Toriola, A. T., Grankvist, K., Agborsangaya, C. B., Lukanova, A., Lehtinen, M., & Surcel, H. M. (2011). Changes in pre-diagnostic serum C-reactive protein concentrations and ovarian cancer risk: A longitudinal study. Annals of Oncology, 22(8), 1916–1921. doi:10.1093/annonc/mdq694.

    Article  CAS  PubMed  Google Scholar 

  46. Lundin, E., Dossus, L., Clendenen, T., Krogh, V., Grankvist, K., Wulff, M., et al. (2009). C-reactive protein and ovarian cancer: A prospective study nested in three cohorts (Sweden, USA, Italy). Cancer Causes & Control, 20(7), 1151–1159. doi:10.1007/s10552-009-9330-2.

    Article  Google Scholar 

  47. Clendenen, T. V., Lundin, E., Zeleniuch-Jacquotte, A., Koenig, K. L., Berrino, F., Lukanova, A., et al. (2011). Circulating inflammation markers and risk of epithelial ovarian cancer. Cancer Epidemiology, Biomarkers & Prevention, 20(5), 799–810. doi:10.1158/1055-9965.EPI-10-1180.

    Article  CAS  Google Scholar 

  48. Grivennikov, S. I., Greten, F. R., & Karin, M. (2010). Immunity, inflammation, and cancer. Cell, 140(6), 883–899. doi:10.1016/j.cell.20doi:10.01.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Haskill, S., Becker, S., Fowler, W., & Walton, L. (1982). Mononuclear-cell infiltration in ovarian cancer. I. Inflammatory-cell infiltrates from tumour and ascites material. British Journal of Cancer, 45(5), 728–736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang, L., Conejo-Garcia, J. R., Katsaros, D., Gimotty, P. A., Massobrio, M., Regnani, G., et al. (2003). Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. The New England Journal of Medicine, 348(3), 203–213. doi:10.1056/NEJMoa020177.

    Article  CAS  PubMed  Google Scholar 

  51. Sato, E., Olson, S. H., Ahn, J., Bundy, B., Nishikawa, H., Qian, F., et al. (2005). Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America, 102(51), 18538–18543. doi:10.1073/pnas.0509182102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Leffers, N., Gooden, M. J., de Jong, R. A., Hoogeboom, B. N., ten Hoor, K. A., Hollema, H., et al. (2009). Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunology, Immunotherapy, 58(3), 449–459. doi:10.1007/s00262-008-0583-5.

    Article  PubMed  Google Scholar 

  53. Callahan, M. J., Nagymanyoki, Z., Bonome, T., Johnson, M. E., Litkouhi, B., Sullivan, E. H., et al. (2008). Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer. Clinical Cancer Research, 14(23), 7667–7673. doi:10.1158/1078-0432.CCR-08-0479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Leffers, N., Fehrmann, R. S., Gooden, M. J., Schulze, U. R., Ten Hoor, K. A., Hollema, H., et al. (2010). Identification of genes and pathways associated with cytotoxic T lymphocyte infiltration of serous ovarian cancer. British Journal of Cancer, 103(5), 685–692. doi:10.1038/sj.bjc.6605820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Milne, K., Kobel, M., Kalloger, S. E., Barnes, R. O., Gao, D., Gilks, C. B., et al. (2009). Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PloS One, 4(7), e6412. doi:10.1371/journal.pone.0006412.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Le Page, C., Marineau, A., Bonza, P. K., Rahimi, K., Cyr, L., Labouba, I., et al. (2012). BTN3A2 expression in epithelial ovarian cancer is associated with higher tumor infiltrating T cells and a better prognosis. PloS One, 7(6), e38541. doi:10.1371/journal.pone.0038541.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Kryczek, I., Banerjee, M., Cheng, P., Vatan, L., Szeliga, W., Wei, S., et al. (2009). Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood, 114(6), 1141–1149. doi:10.1182/blood-2009-03-208249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cua, D. J., & Tato, C. M. (2010). Innate IL-17-producing cells: The sentinels of the immune system. Nature Reviews Immunology, 10(7), 479–489. doi:10.1038/nri2800.

    Article  CAS  PubMed  Google Scholar 

  59. Goodell, V., Salazar, L. G., Urban, N., Drescher, C. W., Gray, H., Swensen, R. E., et al. (2006). Antibody immunity to the p53 oncogenic protein is a prognostic indicator in ovarian cancer. Journal of Clinical Oncology, 24(5), 762–768. doi:10.1200/JCO.2005.03.2813.

    Article  CAS  PubMed  Google Scholar 

  60. Knutson, K. L., Krco, C. J., Erskine, C. L., Goodman, K., Kelemen, L. E., Wettstein, P. J., et al. (2006). T-cell immunity to the folate receptor alpha is prevalent in women with breast or ovarian cancer. Journal of Clinical Oncology, 24(26), 4254–4261. doi:10.1200/JCO.2006.05.9311.

    Article  CAS  PubMed  Google Scholar 

  61. Tchabo, N. E., Mhawech-Fauceglia, P., Caballero, O. L., Villella, J., Beck, A. F., Miliotto, A. J., et al. (2009). Expression and serum immunoreactivity of developmentally restricted differentiation antigens in epithelial ovarian cancer. Cancer Immunity, 9, 6.

    PubMed  PubMed Central  Google Scholar 

  62. Dong, H. P., Elstrand, M. B., Holth, A., Silins, I., Berner, A., Trope, C. G., et al. (2006). NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. American Journal of Clinical Pathology, 125(3), 451–458.

    Article  PubMed  Google Scholar 

  63. Nielsen, J. S., Sahota, R. A., Milne, K., Kost, S. E., Nesslinger, N. J., Watson, P. H., et al. (2012). CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clinical Cancer Research, 18(12), 3281–3292. doi:10.1158/1078-0432.CCR-12-0234.

    Article  CAS  PubMed  Google Scholar 

  64. Perussia, B., Chen, Y., & Loza, M. J. (2005). Peripheral NK cell phenotypes: Multiple changing of faces of an adapting, developing cell. Molecular Immunology, 42(4), 385–395. doi:10.1016/j.molimm.2004.07.017.

    Article  CAS  PubMed  Google Scholar 

  65. Gonzalez, S., Lopez-Soto, A., Suarez-Alvarez, B., Lopez-Vazquez, A., & Lopez-Larrea, C. (2008). NKG2D ligands: Key targets of the immune response. Trends in Immunology, 29(8), 397–403. doi:10.1016/j.it.2008.04.007.

    Article  CAS  PubMed  Google Scholar 

  66. Lopez-Larrea, C., Suarez-Alvarez, B., Lopez-Soto, A., Lopez-Vazquez, A., & Gonzalez, S. (2008). The NKG2D receptor: Sensing stressed cells. Trends in Molecular Medicine, 14(4), 179–189. doi:10.1016/j.molmed.2008.02.004.

    Article  CAS  PubMed  Google Scholar 

  67. Li, K., Mandai, M., Hamanishi, J., Matsumura, N., Suzuki, A., Yagi, H., et al. (2009). Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: High expression of ULBP2 is an indicator of poor prognosis. Cancer Immunology, Immunotherapy, 58(5), 641–652. doi:10.1007/s00262-008-0585-3.

    Article  CAS  PubMed  Google Scholar 

  68. Knutson, K. L., Disis, M. L., & Salazar, L. G. (2007). CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunology, Immunotherapy, 56(3), 271–285. doi:10.1007/s00262-006-0194-y.

    Article  PubMed  Google Scholar 

  69. Bluestone, J. A., & Abbas, A. K. (2003). Natural versus adaptive regulatory T cells. Nature Reviews Immunology, 3(3), 253–257. doi:10.1038/nri1032.

    Article  CAS  PubMed  Google Scholar 

  70. Meloni, F., Morosini, M., Solari, N., Passadore, I., Nascimbene, C., Novo, M., et al. (2006). Foxp3 expressing CD4+ CD25+ and CD8+ CD28− T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma. Human Immunology, 67(1–2), 1–12. doi:10.1016/j.humimm.2005.11.005.

    Article  CAS  PubMed  Google Scholar 

  71. Audia, S., Nicolas, A., Cathelin, D., Larmonier, N., Ferrand, C., Foucher, P., et al. (2007). Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: A phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes. Clinical and Experimental Immunology, 150(3), 523–530. doi:10.1111/j.1365-2249.2007.03521.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Li, X., Ye, D. F., Xie, X., Chen, H. Z., & Lu, W. G. (2005). Proportion of CD4+ CD25+ regulatory T cell is increased in the patients with ovarian carcinoma. Cancer Investigation, 23(5), 399–403.

    CAS  PubMed  Google Scholar 

  73. Preston, C. C., Maurer, M. J., Oberg, A. L., Visscher, D. W., Kalli, K. R., Hartmann, L. C., et al. (2013). The ratios of CD8+ T cells to CD4+ CD25+ FOXP3+ and FOXP3− T cells correlate with poor clinical outcome in human serous ovarian cancer. PloS One, 8(11), e80063. doi:10.1371/journal.pone.0080063.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine, 10(9), 942–949. doi:10.1038/nm1093.

    Article  CAS  PubMed  Google Scholar 

  75. Wolf, D., Wolf, A. M., Rumpold, H., Fiegl, H., Zeimet, A. G., Muller-Holzner, E., et al. (2005). The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clinical Cancer Research, 11(23), 8326–8331. doi:10.1158/1078-0432.CCR-05-1244.

    Article  CAS  PubMed  Google Scholar 

  76. Murray, P. J., & Wynn, T. A. (2011). Protective and pathogenic functions of macrophage subsets. Nature Reviews Immunology, 11(11), 723–737. doi:10.1038/nri3073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hagemann, T., Wilson, J., Burke, F., Kulbe, H., Li, N. F., Pluddemann, A., et al. (2006). Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. Journal of Immunology, 176(8), 5023–5032.

    Article  CAS  Google Scholar 

  78. Ko, S. Y., Ladanyi, A., Lengyel, E., & Naora, H. (2014). Expression of the homeobox gene HOXA9 in ovarian cancer induces peritoneal macrophages to acquire an M2 tumor-promoting phenotype. The American Journal of Pathology, 184(1), 271–281. doi:10.1016/j.ajpath.2013.09.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shah, C. A., Allison, K. H., Garcia, R. L., Gray, H. J., Goff, B. A., & Swisher, E. M. (2008). Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: Association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer. Gynecologic Oncology, 109(2), 215–219. doi:10.1016/j.ygyno.2008.01.0doi:10.

    Article  CAS  PubMed  Google Scholar 

  80. Lan, C., Huang, X., Lin, S., Huang, H., Cai, Q., Wan, T., et al. (2013). Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technology in Cancer Research & Treatment, 12(3), 259–267. doi:10.7785/tcrt.2012.500312.

    CAS  Google Scholar 

  81. Karyampudi, L., Lamichhane, P., Scheid, A. D., Kalli, K. R., Shreeder, B., Krempski, J. W., et al. (2014). Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. Cancer Research, 74(11), 2974–2985. doi:10.1158/0008-5472.CAN-13-2564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Fricke, I., & Gabrilovich, D. I. (2006). Dendritic cells and tumor microenvironment: A dangerous liaison. Immunological Investigations, 35(3–4), 459–483. doi:10.1080/08820130600803429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chen, F., Hou, M., Ye, F., Lv, W., & Xie, X. (2009). Ovarian cancer cells induce peripheral mature dendritic cells to differentiate into macrophagelike cells in vitro. International Journal of Gynecological Cancer, 19(9), 1487–1493. doi:10.1111/IGC.0b013e3181bb70c6.

    Article  PubMed  Google Scholar 

  84. Krempski, J., Karyampudi, L., Behrens, M. D., Erskine, C. L., Hartmann, L., Dong, H., et al. (2011). Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer. Journal of Immunology, 186(12), 6905–6913. doi:10.4049/jimmunol.1100274.

    Article  CAS  Google Scholar 

  85. Schmid, M. C., & Varner, J. A. (2010). Myeloid cells in the tumor microenvironment: Modulation of tumor angiogenesis and tumor inflammation. Journal of Oncology, 2010, 201026. doi:10.1155/2010/201026.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Ostrand-Rosenberg, S. (2010). Myeloid-derived suppressor cells: More mechanisms for inhibiting antitumor immunity. Cancer Immunology, Immunotherapy, 59(10), 1593–1600. doi:10.1007/s00262-010-0855-8.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Kerbel, R. S. (2008). Tumor angiogenesis. The New England Journal of Medicine, 358(19), 2039–2049. doi:10.1056/NEJMra0706596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zou, W., Machelon, V., Coulomb-L’Hermin, A., Borvak, J., Nome, F., Isaeva, T., et al. (2001). Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nature Medicine, 7(12), 1339–1346. doi:10.1038/nm1201-1339.

    Article  CAS  PubMed  Google Scholar 

  89. Wei, S., Kryczek, I., Zou, L., Daniel, B., Cheng, P., Mottram, P., et al. (2005). Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Research, 65(12), 5020–5026. doi:10.1158/0008-5472.CAN-04-4043.

    Article  CAS  PubMed  Google Scholar 

  90. Huarte, E., Cubillos-Ruiz, J. R., Nesbeth, Y. C., Scarlett, U. K., Martinez, D. G., Buckanovich, R. J., et al. (2008). Depletion of dendritic cells delays ovarian cancer progression by boosting antitumor immunity. Cancer Research, 68(18), 7684–7691. doi:10.1158/0008-5472.CAN-08-1167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gabrilovich, D. I., & Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology, 9(3), 162–174. doi:10.1038/nri2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Movahedi, K., Guilliams, M., Van den Bossche, J., Van den Bergh, R., Gysemans, C., Beschin, A., et al. (2008). Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood, 111(8), 4233–4244. doi:10.1182/blood-2007-07-099226.

    Article  CAS  PubMed  Google Scholar 

  93. Youn, J. I., Nagaraj, S., Collazo, M., & Gabrilovich, D. I. (2008). Subsets of myeloid-derived suppressor cells in tumor-bearing mice. Journal of Immunology, 181(8), 5791–5802.

    Article  CAS  Google Scholar 

  94. Serafini, P., Borrello, I., & Bronte, V. (2006). Myeloid suppressor cells in cancer: Recruitment, phenotype, properties, and mechanisms of immune suppression. Seminars in Cancer Biology, 16(1), 53–65. doi:10.1016/j.semcancer.2005.07.005.

    Article  CAS  PubMed  Google Scholar 

  95. Yang, R., Cai, Z., Zhang, Y., Yutzy, W. H., Roby, K. F., & Roden, R. B. (2006). CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+ CD11b+ myeloid cells. Cancer Research, 66(13), 6807–6815. doi:10.1158/0008-5472.CAN-05-3755.

    Article  CAS  PubMed  Google Scholar 

  96. Hamanishi, J., Mandai, M., Iwasaki, M., Okazaki, T., Tanaka, Y., Yamaguchi, K., et al. (2007). Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America, 104(9), 3360–3365. doi:10.1073/pnas.0611533104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ghebeh, H., Mohammed, S., Al-Omair, A., Qattan, A., Lehe, C., Al-Qudaihi, G., et al. (2006). The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: Correlation with important high-risk prognostic factors. Neoplasia, 8(3), 190–198. doi:10.1593/neo.05733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Karim, R., Jordanova, E. S., Piersma, S. J., Kenter, G. G., Chen, L., Boer, J. M., et al. (2009). Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clinical Cancer Research, 15(20), 6341–6347. doi:10.1158/1078-0432.CCR-09-1652.

    Article  CAS  PubMed  Google Scholar 

  99. Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008). PD-1 and its ligands in tolerance and immunity. Annual Review of Immunology, 26, 677–704. doi:10.1146/annurev.immunol.26.021607.090331.

    Article  CAS  PubMed  Google Scholar 

  100. Keir, M. E., Francisco, L. M., & Sharpe, A. H. (2007). PD-1 and its ligands in T-cell immunity. Current Opinion in Immunology, 19(3), 309–314. doi:10.1016/j.coi.2007.04.012.

    Article  CAS  PubMed  Google Scholar 

  101. Keir, M. E., Liang, S. C., Guleria, I., Latchman, Y. E., Qipo, A., Albacker, L. A., et al. (2006). Tissue expression of PD-L1 mediates peripheral T cell tolerance. The Journal of Experimental Medicine, 203(4), 883–895. doi:10.1084/jem.20051776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Matsuzaki, J., Gnjatic, S., Mhawech-Fauceglia, P., Beck, A., Miller, A., Tsuji, T., et al. (2010). Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America, 107(17), 7875–7880. doi:10.1073/pnas.1003345107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gubbels, J. A., Belisle, J., Onda, M., Rancourt, C., Migneault, M., Ho, M., et al. (2006). Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Molecular Cancer, 5(1), 50. doi:10.1186/1476-4598-5-50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Patankar, M. S., Jing, Y., Morrison, J. C., Belisle, J. A., Lattanzio, F. A., Deng, Y., et al. (2005). Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Gynecologic Oncology, 99(3), 704–713. doi:10.1016/j.ygyno.2005.07.030.

    Article  CAS  PubMed  Google Scholar 

  105. Gubbels, J. A., Felder, M., Horibata, S., Belisle, J. A., Kapur, A., Holden, H., et al. (2010). MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells. Molecular Cancer, 9, 11. doi:10.1186/1476-4598-9-11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Belisle, J. A., Horibata, S., Jennifer, G. A., Petrie, S., Kapur, A., Andre, S., et al. (2010). Identification of siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes. Molecular Cancer, 9, 118. doi:10.1186/1476-4598-9-118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Krockenberger, M., Dombrowski, Y., Weidler, C., Ossadnik, M., Honig, A., Hausler, S., et al. (2008). Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D. Journal of Immunology, 180(11), 7338–7348.

    Article  CAS  Google Scholar 

  108. Uyttenhove, C., Pilotte, L., Theate, I., Stroobant, V., Colau, D., Parmentier, N., et al. (2003). Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Medicine, 9(10), 1269–1274. doi:10.1038/nm934.

    Article  CAS  PubMed  Google Scholar 

  109. Munn, D. H. (2006). Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation. Current Opinion in Immunology, 18(2), 220–225. doi:10.1016/j.coi.2006.01.002.

    Article  CAS  PubMed  Google Scholar 

  110. Terness, P., Bauer, T. M., Rose, L., Dufter, C., Watzlik, A., Simon, H., et al. (2002). Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: Mediation of suppression by tryptophan metabolites. The Journal of Experimental Medicine, 196(4), 447–457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Munn, D. H., Sharma, M. D., Baban, B., Harding, H. P., Zhang, Y., Ron, D., et al. (2005). GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity, 22(5), 633–642. doi:10.1016/j.immuni.2005.03.013.

    Article  CAS  PubMed  Google Scholar 

  112. Della Chiesa, M., Carlomagno, S., Frumento, G., Balsamo, M., Cantoni, C., Conte, R., et al. (2006). The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood, 108(13), 4118–4125. doi:10.1182/blood-2006-03-006700.

    Article  CAS  PubMed  Google Scholar 

  113. Chiesa, S., Mingueneau, M., Fuseri, N., Malissen, B., Raulet, D. H., Malissen, M., et al. (2006). Multiplicity and plasticity of natural killer cell signaling pathways. Blood, 107(6), 2364–2372. doi:10.1182/blood-2005-08-3504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Frumento, G., Rotondo, R., Tonetti, M., Damonte, G., Benatti, U., & Ferrara, G. B. (2002). Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. The Journal of Experimental Medicine, 196(4), 459–468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Baban, B., Chandler, P. R., Sharma, M. D., Pihkala, J., Koni, P. A., Munn, D. H., et al. (2009). IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. Journal of Immunology, 183(4), 2475–2483. doi:10.4049/jimmunol.0900986.

    Article  CAS  Google Scholar 

  116. Fallarino, F., Grohmann, U., You, S., McGrath, B. C., Cavener, D. R., Vacca, C., et al. (2006). The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. Journal of Immunology, 176(11), 6752–6761.

    Article  CAS  Google Scholar 

  117. Hill, M., Tanguy-Royer, S., Royer, P., Chauveau, C., Asghar, K., Tesson, L., et al. (2007). IDO expands human CD4+ CD25 high regulatory T cells by promoting maturation of LPS-treated dendritic cells. European Journal of Immunology, 37(11), 3054–3062. doi:10.1002/eji.200636704.

    Article  CAS  PubMed  Google Scholar 

  118. Inaba, T., Ino, K., Kajiyama, H., Yamamoto, E., Shibata, K., Nawa, A., et al. (2009). Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecologic Oncology, 115(2), 185–192. doi:10.1016/j.ygyno.2009.07.015.

    Article  CAS  PubMed  Google Scholar 

  119. Okamoto, A., Nikaido, T., Ochiai, K., Takakura, S., Saito, M., Aoki, Y., et al. (2005). Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clinical Cancer Research, 11(16), 6030–6039. doi:10.1158/1078-0432.CCR-04-2671.

    Article  CAS  PubMed  Google Scholar 

  120. Takao, M., Okamoto, A., Nikaido, T., Urashima, M., Takakura, S., Saito, M., et al. (2007). Increased synthesis of indoleamine-2,3-dioxygenase protein is positively associated with impaired survival in patients with serous-type, but not with other types of, ovarian cancer. Oncology Reports, 17(6), 1333–1339.

    CAS  PubMed  Google Scholar 

  121. Zheng, X., Koropatnick, J., Li, M., Zhang, X., Ling, F., Ren, X., et al. (2006). Reinstalling antitumor immunity by inhibiting tumor-derived immunosuppressive molecule IDO through RNA interference. Journal of Immunology, 177(8), 5639–5646.

    Article  CAS  Google Scholar 

  122. Zamanakou, M., Germenis, A. E., & Karanikas, V. (2007). Tumor immune escape mediated by indoleamine 2,3-dioxygenase. Immunology Letters, 111(2), 69–75. doi:10.1016/j.imlet.2007.06.001.

    Article  CAS  PubMed  Google Scholar 

  123. Lob, S., Konigsrainer, A., Zieker, D., Brucher, B. L., Rammensee, H. G., Opelz, G., et al. (2009). IDO1 and IDO2 are expressed in human tumors: Levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunology, Immunotherapy, 58(1), 153–157. doi:10.1007/s00262-008-0513-6.

    Article  PubMed  CAS  Google Scholar 

  124. Liu, X., Shin, N., Koblish, H. K., Yang, G., Wang, Q., Wang, K., et al. (2010). Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood, 115(17), 3520–3530. doi:10.1182/blood-2009-09-246124.

    Article  CAS  PubMed  Google Scholar 

  125. Koblish, H. K., Hansbury, M. J., Bowman, K. J., Yang, G., Neilan, C. L., Haley, P. J., et al. (2010). Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Molecular Cancer Therapeutics, 9(2), 489–498. doi:10.1158/1535-7163.MCT-09-0628.

    Article  CAS  PubMed  Google Scholar 

  126. Soliman, H., Mediavilla-Varela, M., & Antonia, S. (2010). Indoleamine 2,3-dioxygenase: Is it an immune suppressor? Cancer Journal, 16(4), 354–359.

    Article  CAS  Google Scholar 

  127. Cady, S. G., & Sono, M. (1991). 1-Methyl-DL-tryptophan, beta-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Archives of Biochemistry and Biophysics, 291(2), 326–333.

    Article  CAS  PubMed  Google Scholar 

  128. Hou, D. Y., Muller, A. J., Sharma, M. D., DuHadaway, J., Banerjee, T., Johnson, M., et al. (2007). Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Research, 67(2), 792–801. doi:10.1158/0008-5472.CAN-06-2925.

    Article  CAS  PubMed  Google Scholar 

  129. Metz, R., Duhadaway, J. B., Kamasani, U., Laury-Kleintop, L., Muller, A. J., & Prendergast, G. C. (2007). Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Research, 67(15), 7082–7087. doi:10.1158/0008-5472.CAN-07-1872.

    Article  CAS  PubMed  Google Scholar 

  130. Opitz, C. A., Litzenburger, U. M., Sahm, F., Ott, M., Tritschler, I., Trump, S., et al. (2011). An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature, 478(7368), 197–203. doi:10.1038/nature10491.

    Article  CAS  PubMed  Google Scholar 

  131. Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., et al. (2008). Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature, 453(7191), 65–71. doi:10.1038/nature06880.

    Article  CAS  PubMed  Google Scholar 

  132. Pilotte, L., Larrieu, P., Stroobant, V., Colau, D., Dolusic, E., Frederick, R., et al. (2012). Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proceedings of the National Academy of Sciences of the United States of America, 109(7), 2497–2502. doi:10.1073/pnas.1113873109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kulbe, H., Chakravarty, P., Leinster, D. A., Charles, K. A., Kwong, J., Thompson, R. G., et al. (2012). A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Cancer Research, 72(1), 66–75. doi:10.1158/0008-5472.CAN-11-2178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kulbe, H., Thompson, R., Wilson, J. L., Robinson, S., Hagemann, T., Fatah, R., et al. (2007). The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Research, 67(2), 585–592. doi:10.1158/0008-5472.CAN-06-2941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Balkwill, F. (2002). Tumor necrosis factor or tumor promoting factor? Cytokine & Growth Factor Reviews, 13(2), 135–141. doi:10.1016/s1359-6101(01)00020-x.

    Article  CAS  Google Scholar 

  136. Anderson, G. M., Nakada, M. T., & DeWitte, M. (2004). Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer. Current Opinion in Pharmacology, 4(4), 314–320. doi:10.1016/j.coph.2004.04.004.

    Article  CAS  PubMed  Google Scholar 

  137. Penson, R. T., Kronish, K., Duan, Z., Feller, A. J., Stark, P., Cook, S. E., et al. (2000). Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. International Journal of Gynecological Cancer, 10(1), 33–41. doi:10.1046/j.1525-1438.2000.00003.x.

    Article  PubMed  Google Scholar 

  138. Guo, Y., Xu, F., Lu, T., Duan, Z., & Zhang, Z. (2012). Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treatment Reviews, 38(7), 904–909. doi:10.1016/j.ctrv.2012.04.007.

    Article  CAS  PubMed  Google Scholar 

  139. Coward, J., Kulbe, H., Chakravarty, P., Leader, D., Vassileva, V., Leinster, D. A., et al. (2011). Interleukin-6 as a therapeutic target in human ovarian cancer. Clinical Cancer Research, 17(18), 6083–6096. doi:10.1158/1078-0432.CCR-11-0945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Duan, Z., Foster, R., Bell, D. A., Mahoney, J., Wolak, K., Vaidya, A., et al. (2006). Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clinical Cancer Research, 12(17), 5055–5063. doi:10.1158/1078-0432.CCR-06-0861.

    Article  CAS  PubMed  Google Scholar 

  141. Lo, C. W., Chen, M. W., Hsiao, M., Wang, S., Chen, C. A., Hsiao, S. M., et al. (2011). IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Research, 71(2), 424–434. doi:10.1158/0008-5472.CAN-10-1496.

    Article  CAS  PubMed  Google Scholar 

  142. Plante, M., Rubin, S. C., Wong, G. Y., Federici, M. G., Finstad, C. L., & Gastl, G. A. (1994). Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer, 73(7), 1882–1888. doi:10.1002/1097-0142(19940401)73:7<1882::aid-cncr2820730718>3.0.co;2-r.

    Article  CAS  PubMed  Google Scholar 

  143. Yang, L., Wang, L., Lin, H. K., Kan, P. Y., Xie, S., Tsai, M. Y., et al. (2003). Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochemical and Biophysical Research Communications, 305(3), 462–469. doi:10.1016/s0006-291x(03)00792-7.

    Article  CAS  PubMed  Google Scholar 

  144. Wang, T. H., Chan, Y. H., Chen, C. W., Kung, W. H., Lee, Y. S., Wang, S. T., et al. (2006). Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways. Oncogene, 25(35), 4857–4866.

    Article  CAS  PubMed  Google Scholar 

  145. Stone, R. L., Nick, A. M., McNeish, I. A., Balkwill, F., Han, H. D., Bottsford-Miller, J., et al. (2012). Paraneoplastic thrombocytosis in ovarian cancer. The New England Journal of Medicine, 366(7), 610–618. doi:10.1056/NEJMoa1110352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Trikha, M., Corringham, R., Klein, B., & Rossi, J. F. (2003). Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: A review of the rationale and clinical evidence. Clinical Cancer Research, 9(13), 4653–4665.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Barbieri, F., Bajetto, A., & Florio, T. (2010). Role of chemokine network in the development and progression of ovarian cancer: a potential novel pharmacological target. Journal of Oncology, 2010, 426956. doi:10.1155/2010/426956.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Kryczek, I., Lange, A., Mottram, P., Alvarez, X., Cheng, P., Hogan, M., et al. (2005). CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Research, 65(2), 465–472.

    CAS  PubMed  Google Scholar 

  149. Porcile, C., Bajetto, A., Barbieri, F., Barbero, S., Bonavia, R., Biglieri, M., et al. (2005). Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. Experimental Cell Research, 308(2), 241–253. doi:10.1016/j.yexcr.2005.04.024.

    Article  CAS  PubMed  Google Scholar 

  150. Kajiyama, H., Shibata, K., Terauchi, M., Ino, K., Nawa, A., & Kikkawa, F. (2008). Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma. International Journal of Cancer, 122(1), 91–99. doi:10.1002/ijc.23083.

    Article  CAS  PubMed  Google Scholar 

  151. Righi, E., Kashiwagi, S., Yuan, J., Santosuosso, M., Leblanc, P., Ingraham, R., et al. (2011). CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Research, 71(16), 5522–5534. doi:10.1158/0008-5472.CAN-10-3143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Goode, E. L., Maurer, M. J., Sellers, T. A., Phelan, C. M., Kalli, K. R., Fridley, B. L., et al. (2010). Inherited determinants of ovarian cancer survival. Clinical Cancer Research, 16(3), 995–1007. doi:10.1158/1078-0432.CCR-09-2553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Frede, S., Freitag, P., Otto, T., Heilmaier, C., & Fandrey, J. (2005). The proinflammatory cytokine interleukin 1beta and hypoxia cooperatively induce the expression of adrenomedullin in ovarian carcinoma cells through hypoxia inducible factor 1 activation. Cancer Research, 65(11), 4690–4697. doi:10.1158/0008-5472.CAN-04-3877.

    Article  CAS  PubMed  Google Scholar 

  154. Ioana Braicu, E., Mustea, A., Toliat, M. R., Pirvulescu, C., Konsgen, D., Sun, P., et al. (2007). Polymorphism of IL-1alpha, IL-1beta and IL-10 in patients with advanced ovarian cancer: Results of a prospective study with 147 patients. Gynecologic Oncology, 104(3), 680–685. doi:10.1016/j.ygyno.2006.doi:10.014.

    Article  PubMed  CAS  Google Scholar 

  155. Goode, E. L., DeRycke, M., Kalli, K. R., Oberg, A. L., Cunningham, J. M., Maurer, M. J., et al. (2013). Inherited variants in regulatory T cell genes and outcome of ovarian cancer. PloS One, 8(1), e53903. doi:10.1371/journal.pone.0053903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Charbonneau, B., Moysich, K. B., Kalli, K. R., Oberg, A. L., Vierkant, R. A., Fogarty, Z. C., et al. (2014). Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome. Cancer Immunology Research, 2(4), 332–340. doi:10.1158/2326-6066.CIR-13-0136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ayyoub, M., Pignon, P., Classe, J. M., Odunsi, K., & Valmori, D. (2013). CD4+ T effectors specific for the tumor antigen NY-ESO-1 are highly enriched at ovarian cancer sites and coexist with, but are distinct from, tumor-associated treg. Cancer Immunology Research, 1(5), 303–308. doi:10.1158/2326-6066.CIR-13-0062-T.

    Article  CAS  PubMed  Google Scholar 

  158. Wick, D. A., Webb, J. R., Nielsen, J. S., Martin, S. D., Kroeger, D. R., Milne, K., et al. (2014). Surveillance of the tumor mutanome by T cells during progression from primary to recurrent ovarian cancer. Clinical Cancer Research, 20(5), 1125–1134. doi:10.1158/1078-0432.CCR-13-2147.

    Article  CAS  PubMed  Google Scholar 

  159. Ioannides, C. G., Fisk, B., Fan, D., Biddison, W. E., Wharton, J. T., & O’Brian, C. A. (1993). Cytotoxic T cells isolated from ovarian malignant ascites recognize a peptide derived from the HER-2/neu proto-oncogene. Cellular Immunology, 151(1), 225–234. doi:10.1006/cimm.1993.1233.

    Article  PubMed  Google Scholar 

  160. Doherty, J. K., Bond, C., Jardim, A., Adelman, J. P., & Clinton, G. M. (1999). The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proceedings of the National Academy of Sciences of the United States of America, 96(19), 10869–10874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Bookman, M. A., Darcy, K. M., Clarke-Pearson, D., Boothby, R. A., & Horowitz, I. R. (2003). Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: A phase II trial of the gynecologic oncology group. Journal of Clinical Oncology, 21(2), 283–290.

    Article  CAS  PubMed  Google Scholar 

  162. Camilleri-Broet, S., Hardy-Bessard, A. C., Le Tourneau, A., Paraiso, D., Levrel, O., Leduc, B., et al. (2004). HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: A multicenter study of the GINECO group. Annals of Oncology, 15(1), 104–112.

    Article  CAS  PubMed  Google Scholar 

  163. Karaferic, A., Jovanovic, D., & Jelic, S. (2009). Expression of HER2/neu, estrogen and progesterone receptors, CA 125 and CA19-9 on cancer cell membrane in patients with serous and mucinous carcinoma of the ovary. Journal of B.U.ON., 14(4), 635–639.

    CAS  PubMed  Google Scholar 

  164. Tuefferd, M., Couturier, J., Penault-Llorca, F., Vincent-Salomon, A., Broet, P., Guastalla, J. P., et al. (2007). HER2 status in ovarian carcinomas: A multicenter GINECO study of 320 patients. PloS One, 2(11), e1138. doi:10.1371/journal.pone.0001138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Hogdall, E. V., Christensen, L., Kjaer, S. K., Blaakaer, J., Bock, J. E., Glud, E., et al. (2003). Distribution of HER-2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma: From the Danish MALOVA ovarian cancer study. Cancer, 98(1), 66–73. doi:10.1002/cncr.11476.

    Article  CAS  PubMed  Google Scholar 

  166. Baron-Hay, S., Boyle, F., Ferrier, A., & Scott, C. (2004). Elevated serum insulin-like growth factor binding protein-2 as a prognostic marker in patients with ovarian cancer. Clinical Cancer Research, 10(5), 1796–1806.

    Article  CAS  PubMed  Google Scholar 

  167. Lancaster, J. M., Sayer, R. A., Blanchette, C., Calingaert, B., Konidari, I., Gray, J., et al. (2006). High expression of insulin-like growth factor binding protein-2 messenger RNA in epithelial ovarian cancers produces elevated preoperative serum levels. International Journal of Gynecological Cancer, 16(4), 1529–1535. doi:10.1111/j.1525-1438.2006.00623.x.

    Article  CAS  PubMed  Google Scholar 

  168. Wang, H., Rosen, D. G., Wang, H., Fuller, G. N., Zhang, W., & Liu, J. (2006). Insulin-like growth factor-binding protein 2 and 5 are differentially regulated in ovarian cancer of different histologic types. Modern Pathology, 19(9), 1149–1156. doi:10.1038/modpathol.3800637.

    Article  CAS  PubMed  Google Scholar 

  169. Yan, X. J., Tian, Y., Wang, C., Wang, X. L., Di, J. M., & Cheng, J. X. (2009). The expressions and clinical significance of IGFBP-2, -3 in both serum and tumor tissues in patients with epithelial ovarian cancer. Sichuan Da Xue Xue Bao. Yi Xue Ban, 40(4), 639–643.

    CAS  PubMed  Google Scholar 

  170. Kalli, K. R., Krco, C. J., Hartmann, L. C., Goodman, K., Maurer, M. J., Yu, C., et al. (2008). An HLA-DR-degenerate epitope pool detects insulin-like growth factor binding protein 2-specific immunity in patients with cancer. Cancer Research, 68(12), 4893–4901. doi:10.1158/0008-5472.CAN-07-6726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Bafna, S., Singh, A. P., Moniaux, N., Eudy, J. D., Meza, J. L., & Batra, S. K. (2008). MUC4, a multifunctional transmembrane glycoprotein, induces oncogenic transformation of NIH3T3 mouse fibroblast cells. Cancer Research, 68(22), 9231–9238. doi:10.1158/0008-5472.CAN-08-3135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Senapati, S., Sharma, P., Bafna, S., Roy, H. K., & Batra, S. K. (2008). The MUC gene family: Their role in the diagnosis and prognosis of gastric cancer. Histology and Histopathology, 23(12), 1541–1552.

    CAS  PubMed  Google Scholar 

  173. Chauhan, S. C., Singh, A. P., Ruiz, F., Johansson, S. L., Jain, M., Smith, L. M., et al. (2006). Aberrant expression of MUC4 in ovarian carcinoma: Diagnostic significance alone and in combination with MUC1 and MUC16 (CA125). Modern Pathology, 19(10), 1386–1394. doi:10.1038/modpathol.3800646.

    Article  CAS  PubMed  Google Scholar 

  174. Singh, A. P., Chauhan, S. C., Bafna, S., Johansson, S. L., Smith, L. M., Moniaux, N., et al. (2006). Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas. The Prostate, 66(4), 421–429. doi:10.1002/pros.20372.

    Article  CAS  PubMed  Google Scholar 

  175. Bast, R. C., Jr., Xu, F. J., Yu, Y. H., Barnhill, S., Zhang, Z., & Mills, G. B. (1998). CA 125: The past and the future. The International Journal of Biological Markers, 13(4), 179–187.

    CAS  PubMed  Google Scholar 

  176. Yin, B. W., & Lloyd, K. O. (2001). Molecular cloning of the CA125 ovarian cancer antigen: Identification as a new mucin, MUC16. The Journal of Biological Chemistry, 276(29), 27371–27375. doi:10.1074/jbc.M103554200.

    Article  CAS  PubMed  Google Scholar 

  177. Ponnusamy, M. P., Lakshmanan, I., Jain, M., Das, S., Chakraborty, S., Dey, P., et al. (2010). MUC4 mucin-induced epithelial to mesenchymal transition: A novel mechanism for metastasis of human ovarian cancer cells. Oncogene, 29(42), 5741–5754. doi:10.1038/onc.20doi:10.309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Terry, K. L., Titus-Ernstoff, L., McKolanis, J. R., Welch, W. R., Finn, O. J., & Cramer, D. W. (2007). Incessant ovulation, mucin 1 immunity, and risk for ovarian cancer. Cancer Epidemiology, Biomarkers & Prevention, 16(1), 30–35. doi:10.1158/1055-9965.EPI-06-0688.

    Article  CAS  Google Scholar 

  179. Oei, A. L., Moreno, M., Verheijen, R. H., Sweep, F. C., Thomas, C. M., Massuger, L. F., et al. (2008). Induction of IgG antibodies to MUC1 and survival in patients with epithelial ovarian cancer. International Journal of Cancer, 123(8), 1848–1853. doi:10.1002/ijc.23725.

    Article  CAS  PubMed  Google Scholar 

  180. Plisiecka-Halasa, J., Dansonka-Mieszkowska, A., Kraszewska, E., Danska-Bidzinska, A., & Kupryjanczyk, J. (2008). Loss of heterozygosity, microsatellite instability and TP53 gene status in ovarian carcinomas. Anticancer Research, 28(2A), 989–996.

    CAS  PubMed  Google Scholar 

  181. Corney, D. C., Flesken-Nikitin, A., Choi, J., & Nikitin, A. Y. (2008). Role of p53 and Rb in ovarian cancer. Advances in Experimental Medicine and Biology, 622, 99–117. doi:10.1007/978-0-387-68969-2_9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lambeck, A., Leffers, N., Hoogeboom, B. N., Sluiter, W., Hamming, I., Klip, H., et al. (2007). P53-specific T cell responses in patients with malignant and benign ovarian tumors: Implications for p53 based immunotherapy. International Journal of Cancer, 121(3), 606–614. doi:10.1002/ijc.227doi:10.

    Article  CAS  PubMed  Google Scholar 

  183. Valmori, D., Qian, F., Ayyoub, M., Renner, C., Merlo, A., Gnjatic, S., et al. (2006). Expression of synovial sarcoma X (SSX) antigens in epithelial ovarian cancer and identification of SSX-4 epitopes recognized by CD4+ T cells. Clinical Cancer Research, 12(2), 398–404. doi:10.1158/1078-0432.CCR-05-1902.

    Article  CAS  PubMed  Google Scholar 

  184. Zhang, S., Zhou, X., Yu, H., & Yu, Y. (2010). Expression of tumor-specific antigen MAGE, GAGE and BAGE in ovarian cancer tissues and cell lines. BMC Cancer, 10, 163. doi:10.1186/1471-2407-10-163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Hofmann, M., & Ruschenburg, I. (2002). mRNA detection of tumor-rejection genes BAGE, GAGE, and MAGE in peritoneal fluid from patients with ovarian carcinoma as a potential diagnostic tool. Cancer, 96(3), 187–193. doi:10.1002/cncr.10622.

    Article  CAS  PubMed  Google Scholar 

  186. Straughn, J. M., Jr., Shaw, D. R., Guerrero, A., Bhoola, S. M., Racelis, A., Wang, Z., et al. (2004). Expression of sperm protein 17 (Sp17) in ovarian cancer. International Journal of Cancer, 108(6), 805–811. doi:10.1002/ijc.11617.

    Article  CAS  PubMed  Google Scholar 

  187. Odunsi, K., Jungbluth, A. A., Stockert, E., Qian, F., Gnjatic, S., Tammela, J., et al. (2003). NY-ESO-1 and LAGE-1 cancer-testis antigens are potential targets for immunotherapy in epithelial ovarian cancer. Cancer Research, 63(18), 6076–6083.

    CAS  PubMed  Google Scholar 

  188. Agarwal, S., Saini, S., Parashar, D., Verma, A., Sinha, A., Jagadish, N., et al. (2013). The novel cancer-testis antigen A-kinase anchor protein 4 (AKAP4) is a potential target for immunotherapy of ovarian serous carcinoma. Oncoimmunology, 2(5), e24270. doi:10.4161/onci.24270.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Li, F. Q., Han, Y. L., Liu, Q., Wu, B., Huang, W. B., & Zeng, S. Y. (2009). Overexpression of human sperm protein 17 increases migration and decreases the chemosensitivity of human epithelial ovarian cancer cells. BMC Cancer, 9, 323. doi:10.1186/1471-2407-9-323.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Brown Jones, M., Neuper, C., Clayton, A., Mariani, A., Konecny, G., Thomas, M. B., et al. (2008). Rationale for folate receptor alpha targeted therapy in “high risk” endometrial carcinomas. International Journal of Cancer, 123(7), 1699–1703.

    Article  PubMed  CAS  Google Scholar 

  191. Dainty, L. A., Risinger, J. I., Morrison, C., Chandramouli, G. V., Bidus, M. A., Zahn, C., et al. (2007). Overexpression of folate binding protein and mesothelin are associated with uterine serous carcinoma. Gynecologic Oncology, 105(3), 563–570. doi:10.1016/j.ygyno.2006.doi:10.063.

    Article  CAS  PubMed  Google Scholar 

  192. Elnakat, H., & Ratnam, M. (2006). Role of folate receptor genes in reproduction and related cancers. Frontiers in Bioscience, 11, 506–519.

    Article  CAS  PubMed  Google Scholar 

  193. Parker, N., Turk, M. J., Westrick, E., Lewis, J. D., Low, P. S., & Leamon, C. P. (2005). Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Analytical Biochemistry, 338(2), 284–293. doi:10.1016/j.ab.2004.12.026.

    Article  CAS  PubMed  Google Scholar 

  194. Kelemen, L. E. (2006). The role of folate receptor alpha in cancer development, progression and treatment: Cause, consequence or innocent bystander? International Journal of Cancer, 119(2), 243–250. doi:10.1002/ijc.21712.

    Article  CAS  PubMed  Google Scholar 

  195. Peoples, G. E., Anderson, B. W., Fisk, B., Kudelka, A. P., Wharton, J. T., & Ioannides, C. G. (1998). Ovarian cancer-associated lymphocyte recognition of folate binding protein peptides. Annals of Surgical Oncology, 5(8), 743–750.

    Article  CAS  PubMed  Google Scholar 

  196. Peoples, G. E., Anderson, B. W., Lee, T. V., Murray, J. L., Kudelka, A. P., Wharton, J. T., et al. (1999). Vaccine implications of folate binding protein, a novel cytotoxic T lymphocyte-recognized antigen system in epithelial cancers. Clinical Cancer Research, 5(12), 4214–4223.

    CAS  PubMed  Google Scholar 

  197. Tassi, R. A., Calza, S., Ravaggi, A., Bignotti, E., Odicino, F. E., Tognon, G., et al. (2009). Mammaglobin B is an independent prognostic marker in epithelial ovarian cancer and its expression is associated with reduced risk of disease recurrence. BMC Cancer, 9, 253. doi:10.1186/1471-2407-9-253.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Tassi, R. A., Bignotti, E., Falchetti, M., Calza, S., Ravaggi, A., Rossi, E., et al. (2008). Mammaglobin B expression in human endometrial cancer. International Journal of Gynecological Cancer, 18(5), 1090–1096. doi:10.1111/j.1525-1438.2007.01137.x.

    Article  CAS  PubMed  Google Scholar 

  199. Tassi, R. A., Bignotti, E., Rossi, E., Falchetti, M., Donzelli, C., Calza, S., et al. (2007). Overexpression of mammaglobin B in epithelial ovarian carcinomas. Gynecologic Oncology, 105(3), 578–585. doi:10.1016/j.ygyno.2007.01.043.

    Article  CAS  PubMed  Google Scholar 

  200. Bellone, S., Tassi, R., Betti, M., English, D., Cocco, E., Gasparrini, S., et al. (2013). Mammaglobin B (SCGB2A1) is a novel tumour antigen highly differentially expressed in all major histological types of ovarian cancer: Implications for ovarian cancer immunotherapy. British Journal of Cancer, 109(2), 462–471. doi:10.1038/bjc.2013.315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Pastan, I., & Hassan, R. (2014). Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Research, 74, 2907–2912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Frierson, H. F., Jr., Moskaluk, C. A., Powell, S. M., Zhang, H., Cerilli, L. A., Stoler, M. H., et al. (2003). Large-scale molecular and tissue microarray analysis of mesothelin expression in common human carcinomas. Human Pathology, 34(6), 605–609.

    Article  CAS  PubMed  Google Scholar 

  203. Ho, M., Hassan, R., Zhang, J., Wang, Q. C., Onda, M., Bera, T., et al. (2005). Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients. Clinical Cancer Research, 11(10), 3814–3820. doi:10.1158/1078-0432.CCR-04-2304.

    Article  CAS  PubMed  Google Scholar 

  204. Cheng, W. F., Huang, C. Y., Chang, M. C., Hu, Y. H., Chiang, Y. C., Chen, Y. L., et al. (2009). High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. British Journal of Cancer, 100(7), 1144–1153. doi:10.1038/sj.bjc.6604964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Kalli, K. R. (2007). MORAb-003, a fully humanized monoclonal antibody against the folate receptor alpha, for the potential treatment of epithelial ovarian cancer. Current Opinion in Investigational Drugs, 8(12), 1067–1073.

    CAS  PubMed  Google Scholar 

  206. Ebel, W., Routhier, E. L., Foley, B., Jacob, S., McDonough, J. M., Patel, R. K., et al. (2007). Preclinical evaluation of MORAb-003, a humanized monoclonal antibody antagonizing folate receptor-alpha. Cancer Immunity, 7, 6.

    PubMed  PubMed Central  Google Scholar 

  207. Smith-Jones, P. M., Pandit-Taskar, N., Cao, W., O’Donoghue, J., Philips, M. D., Carrasquillo, J., et al. (2008). Preclinical radioimmunotargeting of folate receptor alpha using the monoclonal antibody conjugate DOTA-MORAb-003. Nuclear Medicine and Biology, 35(3), 343–351. doi:10.1016/j.nucmedbio.2007.12.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Armstrong, D. K., Coleman, R., White, A. J., Bicher, A., Gibbon, D. G., Old, L. J., et al. (2009). Efficacy and safety of farletuzumab, a humanized monoclonal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: Preliminary data from a phase-2 study. European Journal of Cancer, 7(2 Suppl), 450.

    Article  Google Scholar 

  209. White, A.J., Coleman, R., Armstrong, D.K., Glenn D., Bicher, A., Richards, D.A., et al. (2010). Efficacy and safety of farletuzumab, a humanized monoclonal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: Final data from a multicenter phase II study. Journal of Clinical Oncology, 28(15_Suppl).

  210. Spannuth, W. A., Sood, A. K., & Coleman, R. L. (2010). Farletuzumab in epithelial ovarian carcinoma. Expert Opinion on Biological Therapy, 10(3), 431–437. doi:10.1517/14712591003592069.

    Article  CAS  PubMed  Google Scholar 

  211. Hudis, C. A. (2007). Trastuzumab—Mechanism of action and use in clinical practice. The New England Journal of Medicine, 357(1), 39–51. doi:10.1056/NEJMra043186.

    Article  CAS  PubMed  Google Scholar 

  212. Ray-Coquard, I., Guastalla, J. P., Allouache, D., Combe, M., Weber, B., Cretin, J., et al. (2008). HER2 overexpression/amplification and Trastuzumab treatment in advanced ovarian cancer: A GINECO phase II study. Clinical Ovarian Cancer, 1(1), 54–59.

    Article  CAS  Google Scholar 

  213. McAlpine, J. N., Wiegand, K. C., Vang, R., Ronnett, B. M., Adamiak, A., Kobel, M., et al. (2009). HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. BMC Cancer, 9, 433. doi:10.1186/1471-2407-9-433.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. Gordon, M. S., Matei, D., Aghajanian, C., Matulonis, U. A., Brewer, M., Fleming, G. F., et al. (2006). Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: Potential predictive relationship with tumor HER2 activation status. Journal of Clinical Oncology, 24(26), 4324–4332. doi:10.1200/JCO.2005.05.4221.

    Article  CAS  PubMed  Google Scholar 

  215. Takai, N., Jain, A., Kawamata, N., Popoviciu, L. M., Said, J. W., Whittaker, S., et al. (2005). 2C4, a monoclonal antibody against HER2, disrupts the HER kinase signaling pathway and inhibits ovarian carcinoma cell growth. Cancer, 104(12), 2701–2708. doi:10.1002/cncr.21533.

    Article  CAS  PubMed  Google Scholar 

  216. Makhija, S., Amler, L. C., Glenn, D., Ueland, F. R., Gold, M. A., Dizon, D. S., et al. (2010). Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Journal of Clinical Oncology, 28(7), 1215–1223. doi:10.1200/JCO.2009.22.3354.

    Article  CAS  PubMed  Google Scholar 

  217. Kaye, S. B., Poole, C. J., Danska-Bidzinska, A., Gianni, L., Del Conte, G., Gorbunova, V., et al. (2013). A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed, platinum-sensitive ovarian cancer. Annals of Oncology, 24(1), 145–152. doi:10.1093/annonc/mds282.

    Article  CAS  PubMed  Google Scholar 

  218. Langdon, S. P., Faratian, D., Nagumo, Y., Mullen, P., & Harrison, D. J. (2010). Pertuzumab for the treatment of ovarian cancer. Expert Opinion on Biological Therapy, 10(7), 1113–1120. doi:10.1517/14712598.20doi:10.487062.

    Article  CAS  PubMed  Google Scholar 

  219. Grisham, R. N., Berek, J., Pfisterer, J., & Sabbatini, P. (2011). Abagovomab: An anti-idiotypic CA-125 targeted immunotherapeutic agent for ovarian cancer. Immunotherapy, 3(2), 153–162. doi:10.2217/imt.doi:10.100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Wagner, U., Kohler, S., Reinartz S., Giffels P., Huober J., Renke K., et al. (2001). Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: Immune responses and survival in palliative treatment. See The biology behind: K. A. Foon and M. Bhattacharya-Chatterjee, Are solid tumor anti-idiotype vaccines ready for prime time? Clin. Cancer Res., 7:1112–1115, 2001. Clinical Cancer Research 7(5), 1154–1162.

  221. Sabbatini, P., Harter, P., Scambia, G., Sehouli, J., Meier, W., Wimberger, P., et al. (2013). Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: A phase III trial of the AGO OVAR, COGI, GINECO, and GEICO–the MIMOSA study. Journal of Clinical Oncology, 31(12), 1554–1561. doi:10.1200/JCO.2012.46.4057.

    Article  CAS  PubMed  Google Scholar 

  222. Berek, J., Taylor, P., McGuire, W., Smith, L. M., Schultes, B., & Nicodemus, C. F. (2009). Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer. Journal of Clinical Oncology, 27(3), 418–425. doi:10.1200/JCO.2008.17.8400.

    Article  CAS  PubMed  Google Scholar 

  223. Ehlen, T. G., Hoskins, P. J., Miller, D., Whiteside, T. L., Nicodemus, C. F., Schultes, B. C., et al. (2005). A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer. International Journal of Gynecological Cancer, 15(6), 1023–1034. doi:10.1111/j.1525-1438.2005.00483.x.

    Article  CAS  PubMed  Google Scholar 

  224. Berek, J. S., Taylor, P. T., Gordon, A., Cunningham, M. J., Finkler, N., Orr, J., Jr., et al. (2004). Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer. Journal of Clinical Oncology, 22(17), 3507–3516. doi:10.1200/JCO.2004.09.016.

    Article  CAS  PubMed  Google Scholar 

  225. Ruf, P., Gires, O., Jager, M., Fellinger, K., Atz, J., & Lindhofer, H. (2007). Characterisation of the new EpCAM-specific antibody HO-3: Implications for trifunctional antibody immunotherapy of cancer. British Journal of Cancer, 97(3), 315–321. doi:10.1038/sj.bjc.6603881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Burges, A., Wimberger, P., Kumper, C., Gorbounova, V., Sommer, H., Schmalfeldt, B., et al. (2007). Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: A phase I/II study. Clinical Cancer Research, 13(13), 3899–3905. doi:10.1158/1078-0432.CCR-06-2769.

    Article  CAS  PubMed  Google Scholar 

  227. Heiss, M. M., Murawa, P., Koralewski, P., Kutarska, E., Kolesnik, O. O., Ivanchenko, V. V., et al. (2010). The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. International Journal of Cancer, 127(9), 2209–2221. doi:10.1002/ijc.25423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Baumann, K., Pfisterer, J., Wimberger, P., Burchardi, N., Kurzeder, C., du Bois, A., et al. (2011). Intraperitoneal treatment with the trifunctional bispecific antibody catumaxomab in patients with platinum-resistant epithelial ovarian cancer: A phase IIa study of the AGO study group. Gynecologic Oncology, 123(1), 27–32. doi:10.1016/j.ygyno.2011.06.004.

    Article  CAS  PubMed  Google Scholar 

  229. Rossi, J. F., Negrier, S., James, N. D., Kocak, I., Hawkins, R., Davis, H., et al. (2010). A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. British Journal of Cancer, 103(8), 1154–1162. doi:10.1038/sj.bjc.6605872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Karkera, J., Steiner, H., Li, W., Skradski, V., Moser, P. L., Riethdorf, S., et al. (2011). The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. The Prostate, 71(13), 1455–1465. doi:10.1002/pros.21362.

    Article  CAS  PubMed  Google Scholar 

  231. Fizazi, K., De Bono, J. S., Flechon, A., Heidenreich, A., Voog, E., Davis, N. B., et al. (2012). Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. European Journal of Cancer, 48(1), 85–93. doi:10.1016/j.ejca.2011.doi:10.014.

    Article  CAS  PubMed  Google Scholar 

  232. Dorff, T. B., Goldman, B., Pinski, J. K., Mack, P. C., Lara, P. N., Jr., Van Veldhuizen, P. J., Jr., et al. (2010). Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clinical Cancer Research, 16(11), 3028–3034. doi:10.1158/1078-0432.CCR-09-3122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Angevin, E., Tabernero, J., Elez, E., Cohen, S. J., Bahleda, R., van Laethem, J. L., et al. (2014). A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clinical Cancer Research, 20(8), 2192–2204. doi:10.1158/1078-0432.CCR-13-2200.

    Article  CAS  PubMed  Google Scholar 

  234. Hodi, F. S., Mihm, M. C., Soiffer, R. J., Haluska, F. G., Butler, M., Seiden, M. V., et al. (2003). Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proceedings of the National Academy of Sciences of the United States of America, 100(8), 4712–4717. doi:10.1073/pnas.0830997100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Brahmer, J. R., Tykodi, S. S., Chow, L. Q., Hwu, W. J., Topalian, S. L., Hwu, P., et al. (2012). Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. The New England Journal of Medicine, 366(26), 2455–2465. doi:10.1056/NEJMoa1200694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Knutson, K. L., Wagner, W., & Disis, M. L. (2006). Adoptive T cell therapy of solid cancers. Cancer Immunology, Immunotherapy, 55(1), 96–103. doi:10.1007/s00262-005-0706-1.

    Article  PubMed  Google Scholar 

  237. Kalos, M., & June, C. H. (2013). Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity, 39(1), 49–60. doi:10.1016/j.immuni.2013.07.002.

    Article  CAS  PubMed  Google Scholar 

  238. June, C. H. (2007). Adoptive T cell therapy for cancer in the clinic. The Journal of Clinical Investigation, 117(6), 1466–1476. doi:10.1172/JCI32446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. June, C. H. (2007). Principles of adoptive T cell cancer therapy. The Journal of Clinical Investigation, 117(5), 1204–1212. doi:10.1172/JCI31446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Rosenberg, S. A., & Dudley, M. E. (2009). Adoptive cell therapy for the treatment of patients with metastatic melanoma. Current Opinion in Immunology, 21(2), 233–240. doi:10.1016/j.coi.2009.03.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Kershaw, M. H., Westwood, J. A., Parker, L. L., Wang, G., Eshhar, Z., Mavroukakis, S. A., et al. (2006). A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clinical Cancer Research, 12(20 Pt 1), 6106–6115. doi:10.1158/1078-0432.CCR-06-1183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Dobrzanski, M. J., Rewers-Felkins, K. A., Quinlin, I. S., Samad, K. A., Phillips, C. A., Robinson, W., et al. (2009). Autologous MUC1-specific Th1 effector cell immunotherapy induces differential levels of systemic TReg cell subpopulations that result in increased ovarian cancer patient survival. Clinical Immunology, 133(3), 333–352. doi:10.1016/j.clim.2009.08.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Dobrzanski, M. J., Rewers-Felkins, K. A., Samad, K. A., Quinlin, I. S., Phillips, C. A., Robinson, W., et al. (2012). Immunotherapy with IL-10- and IFN-gamma-producing CD4 effector cells modulate “natural” and “inducible” CD4 TReg cell subpopulation levels: Observations in four cases of patients with ovarian cancer. Cancer Immunology, Immunotherapy, 61(6), 839–854. doi:10.1007/s00262-011-1128-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Wright, S. E., Rewers-Felkins, K. A., Quinlin, I. S., Phillips, C. A., Townsend, M., Philip, R., et al. (2012). Cytotoxic T-lymphocyte immunotherapy for ovarian cancer: A pilot study. Journal of Immunotherapy, 35(2), 196–204. doi:10.1097/CJI.0b013e318243f213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Le, D. T., Brockstedt, D. G., Nir-Paz, R., Hampl, J., Mathur, S., Nemunaitis, J., et al. (2012). A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: Phase I studies of safety and immune induction. Clinical Cancer Research, 18(3), 858–868. doi:10.1158/1078-0432.CCR-11-2121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Melief, C. J., & van der Burg, S. H. (2008). Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nature Reviews Cancer, 8(5), 351–360. doi:10.1038/nrc2373.

    Article  CAS  PubMed  Google Scholar 

  247. Sabbatini, P., Tsuji, T., Ferran, L., Ritter, E., Sedrak, C., Tuballes, K., et al. (2012). Phase I trial of overlapping long peptides from a tumor self-antigen and poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients. Clinical Cancer Research, 18(23), 6497–6508. doi:10.1158/1078-0432.CCR-12-2189.

    Article  CAS  PubMed  Google Scholar 

  248. Kaumaya, P. T., Foy, K. C., Garrett, J., Rawale, S. V., Vicari, D., Thurmond, J. M., et al. (2009). Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors. Journal of Clinical Oncology, 27(31), 5270–5277. doi:10.1200/JCO.2009.22.3883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Hernando, J. J., Park, T. W., Fischer, H. P., Zivanovic, O., Braun, M., Polcher, M., et al. (2007). Vaccination with dendritic cells transfected with mRNA-encoded folate-receptor-alpha for relapsed metastatic ovarian cancer. The Lancet Oncology, 8(5), 451–454. doi:10.1016/S1470-2045(07)70142-0.

    Article  PubMed  Google Scholar 

  250. Zum Buschenfelde, C. M., Hermann, C., Schmidt, B., Peschel, C., & Bernhard, H. (2002). Antihuman epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab enhances cytolytic activity of class I-restricted HER2-specific T lymphocytes against HER2-overexpressing tumor cells. Cancer Research, 62(8), 2244–2247.

    PubMed  Google Scholar 

  251. Disis, M. L., Wallace, D. R., Gooley, T. A., Dang, Y., Slota, M., Lu, H., et al. (2009). Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. Journal of Clinical Oncology, 27(28), 4685–4692. doi:10.1200/JCO.2008.20.6789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Muraoka-Cook, R. S., Dumont, N., & Arteaga, C. L. (2005). Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clinical Cancer Research, 11(2 Pt 2), 937s–943s.

    CAS  PubMed  Google Scholar 

  253. Halder, S. K., Beauchamp, R. D., & Datta, P. K. (2005). A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia, 7(5), 509–521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. von Boehmer, H. (2005). Mechanisms of suppression by suppressor T cells. Nature Immunology, 6(4), 338–344. doi:10.1038/ni1180.

    Article  CAS  Google Scholar 

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Acknowledgments

This work is supported by P50-CA136393 (KLK), a grant from the Marsha Rivkin Center for Ovarian Cancer Research and support from the Mayo Graduate School (PL). The authors gratefully acknowledge the expert editorial assistance of Shaundia White of the Vaccine and Gene Therapy Institute of Florida.

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Correspondence to Keith L. Knutson.

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This article has been retracted at the request of the authors and in agreement with the Editors in Chief. The article contains large portions of text that have been duplicated from the articles:

1. Immunity and immune suppression in human ovarian cancer Claudia C Preston, Ellen L Goode, Lynn C Hartmann, Kimberly R Kalli, and Keith L Knutson Immunotherapy. 2011 Apr. 3(4): 539–556, DOI 10.2217/imt.11.20

2. The Immune System in the Pathogenesis of Ovarian Cancer Bridget Charbonneau, Ellen L. Goode, Kimberly R. Kalli, Keith L. Knutson, and Melissa S. DeRycke Crit Rev Immunol. 2013; 33(2): 137–164, DOI: 10.1615/CritRevImmunol.2013006813

An erratum to this article can be found online at http://dx.doi.org/10.1007/s10555-016-9627-z.

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Knutson, K.L., Karyampudi, L., Lamichhane, P. et al. RETRACTED ARTICLE: Targeted immune therapy of ovarian cancer. Cancer Metastasis Rev 34, 53–74 (2015). https://doi.org/10.1007/s10555-014-9540-2

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