International Journal of Clinical Oncology

, Volume 21, Issue 3, pp 456–461 | Cite as

Anti-PD-L1/PD-1 immune therapies in ovarian cancer: basic mechanism and future clinical application

  • Masaki Mandai
  • Junzo Hamanishi
  • Kaoru Abiko
  • Noriomi Matsumura
  • Tsukasa Baba
  • Ikuo Konishi
Invited Review Article

Abstract

Tumor immune therapy, especially anti-programmed cell death ligand-1/programmed cell death-1 (PD-L1/PD-1) treatment, is currently the focus of substantial attention. Ovarian cancer is the leading cause of mortality from gynecological malignancies, and novel treatment modalities, including immune therapy, are needed. However, a basic understanding of tumor immunity associated with the PD-L1/PD-1 signal has only recently emerged. In this review, we first discuss the importance of local tumor immunity, which affects the clinical outcome of ovarian cancer. We subsequently provide an overview of the basic findings regarding how the PD-L1/PD-1 signal influences local tumor immunity in ovarian cancer. Finally, we discuss what is needed to apply immune therapy in future clinical medicine.

Keywords

Ovarian cancer Immunotherapy PD-L1/PD-1 Immune checkpoint inhibitor 

References

  1. 1.
    Burger RA, Brady MF, Bookman MA et al (2011) Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365(26):2473–2483CrossRefPubMedGoogle Scholar
  2. 2.
    Oza AM, Cook AD, Pfisterer J et al (2015) ICON7 trial investigators. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 16(8):928–936CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Aghajanian C, Goff B, Nycum LR et al (2015) Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol 139(1):10–16CrossRefPubMedGoogle Scholar
  4. 4.
    Poveda AM, Selle F, Hilpert F et al (2015) Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort of the randomized phase III AURELIA trial. J Clin Oncol 33(32):3836–3838CrossRefPubMedGoogle Scholar
  5. 5.
    Ledermann J, Harter P, Gourley C et al (2014) Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15(8):852–861CrossRefPubMedGoogle Scholar
  6. 6.
    Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8(6):467–477CrossRefPubMedGoogle Scholar
  7. 7.
    Hamanishi J, Mandai M, Iwasaki M et al (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104(9):3360–3365CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Okazaki T, Chikuma S, Iwai Y et al (2013) A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 14(12):1212–1218CrossRefPubMedGoogle Scholar
  9. 9.
    Sui X, Ma J, Han W et al (2015) The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget 6(23):19393–19404CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hamid O, Robert C, Daud A et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hamanishi J, Mandai M, Ikeda T et al (2015) Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol 33(34):4015–4022CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213CrossRefPubMedGoogle Scholar
  15. 15.
    Sato E, Olson SH, Ahn J et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Vermeij R, de Bock GH, Leffers N et al (2011) Tumor-infiltrating cytotoxic T lymphocytes as independent prognostic factor in epithelial ovarian cancer with Wilms tumor protein 1 overexpression. J Immunother 34(6):516–523CrossRefPubMedGoogle Scholar
  17. 17.
    Bachmayr-Heyda A, Aust S, Heinze G et al (2013) Prognostic impact of tumor infiltrating CD8+ T cells in association with cell proliferation in ovarian cancer patients—a study of the OVCAD consortium. BMC Cancer 17(13):422CrossRefGoogle Scholar
  18. 18.
    Zhang Z, Huang J, Zhang C et al (2015) Infiltration of dendritic cells and T lymphocytes predicts favorable outcome in epithelial ovarian cancer. Cancer Gene Ther 22(4):198–206CrossRefPubMedGoogle Scholar
  19. 19.
    Kooi S, Zhang HZ, Patenia R et al (1996) HLA class I expression on human ovarian carcinoma cells correlates with T-cell infiltration in vivo and T-cell expansion in vitro in low concentrations of recombinant interleukin-2. Cell Immunol 174(2):116–128CrossRefPubMedGoogle Scholar
  20. 20.
    Maine CJ, Aziz NH, Chatterjee J et al (2014) Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer. Cancer Immunol Immunother 63(3):215–224CrossRefPubMedGoogle Scholar
  21. 21.
    Webb JR, Milne K, Watson P et al (2014) Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin Cancer Res 20(2):434–444CrossRefPubMedGoogle Scholar
  22. 22.
    Abiko K, Mandai M, Hamanishi J et al (2013) PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. Clin Cancer Res 19(6):1363–1374CrossRefPubMedGoogle Scholar
  23. 23.
    Abiko K, Matsumura N, Hamanishi J et al (2015) IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 112(9):1501–1509CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Peng W, Liu C, Xu C et al (2012) PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res 72(20):5209–5218CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ascierto PA (2015) Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma. Cancer Immunol Immunother 64(3):271–274CrossRefPubMedGoogle Scholar
  26. 26.
    Duraiswamy J, Kaluza KM, Freeman GJ et al (2013) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 73(12):3591–3603CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Guo Z, Wang X, Cheng D et al (2014) PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One 9(2):e89350CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wei H, Zhao L, Li W et al (2013) Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin. PLoS One 8(12):e84927CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lu L, Xu X, Zhang B et al (2014) Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. J Transl Med 7(12):36CrossRefGoogle Scholar
  30. 30.
    Peng J, Hamanishi J, Matsumura N et al (2015) Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res 75(23):5034–5045CrossRefPubMedGoogle Scholar
  31. 31.
    Guo Z, Wang H, Meng F et al (2015) Combined Trabectedin and anti-PD1 antibody produces a synergistic antitumor effect in a murine model of ovarian cancer. J Transl Med 29(13):247CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2016

Authors and Affiliations

  • Masaki Mandai
    • 1
  • Junzo Hamanishi
    • 2
  • Kaoru Abiko
    • 2
  • Noriomi Matsumura
    • 2
  • Tsukasa Baba
    • 2
  • Ikuo Konishi
    • 2
  1. 1.Department of Obstetrics and Gynecology, Faculty of MedicineKinki UniversityOsaka-SayamaJapan
  2. 2.Department of Gynecology and ObstetricsKyoto University Graduate School of MedicineKyotoJapan

Personalised recommendations