Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Translational Therapeutics

Dynamic host immunity and PD-L1/PD-1 blockade efficacy: developments after “IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer”

British Journal of Cancer volume 128, pages 461–467 (2023)Cite this article

Subjects

Abstract

In the article titled “IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer” in 2015, we showed that PD-L1 expression is induced by IFN-γ from lymphocytes in the tumour microenvironment. This article proposed that PD-L1 expression in cancer cells is not stable but varies among cases, or even within a case, which is influenced by the stromal infiltration of cytotoxic lymphocytes. Immune-checkpoint inhibitors, especially anti-PD-1/PD-L1 therapies, are now widely used to treat various types of cancer. Predictive biomarkers for the efficacy of immune-checkpoint inhibitors include PD-L1 expression, MSI/mismatch repair deficiency and high tumour mutation burden. However, clinical trials have proven that their use in ovarian cancer is still challenging. Reliable biomarkers and new treatment strategies may be sought by elucidating the complex immune microenvironment of ovarian cancer. Although the interaction between cytotoxic lymphocytes and PD-1/PD-L1 on tumour cells is at the centre of therapeutic targets, other immune checkpoints and various immunosuppressive cells also play important roles in ovarian cancer. Targeting these role players in combination with PD-1/PD-L1 blockade may be a promising therapeutic strategy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Unidirectional interaction of ovarian cancer cells and CTLs.
Fig. 2: Bidirectional interaction of ovarian cancer cells and CTLs.
Fig. 3: Multi-directional interaction of ovarian cancer microenvironment.

Similar content being viewed by others

Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

References

  1. Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, et al. IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer. 2015;112:1501–1509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Topalian SL, Hodi FS, Brahmer J,R, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Eng J Med. 2012;366:2443–54.

    Article  CAS  Google Scholar 

  3. Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33:4015–22.

    Article  CAS  PubMed  Google Scholar 

  5. Iwai Y, Yoshida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002;99:12293–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51.

    Article  CAS  PubMed  Google Scholar 

  7. Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14:1212–8.

    Article  CAS  PubMed  Google Scholar 

  8. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38:1–10.

    Article  CAS  PubMed  Google Scholar 

  10. O’Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, Acosta ADJ, et al. Pembrolizumab in Patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. 2022;40:752–61.

    Article  PubMed  Google Scholar 

  11. Marcus L, Fashoyin-Aje LA, Donoghue M, Yuan M, Rodriguez L, Gallagher PS, et al. FDA Approval Summary: Pembrolizumab for the treatment of tumor mutational burden-high solid tumors. Clin Cancer Res. 2021;27:4685–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Makker V, Colombo N, Herráez AC, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386:437–48.

    Article  CAS  PubMed  Google Scholar 

  13. Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Ronnie Shapira-Frommer R, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856–67.

    Article  CAS  PubMed  Google Scholar 

  14. Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, et al. Survival with cemiplimab in recurrent cervical cancer. N Engl J Med. 2022;386:544–55.

    Article  CAS  PubMed  Google Scholar 

  15. Moore KN, Bookman M, Sehouli J, Miller A, Anderson C, Scambia G, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol. 2021;39:1842–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hamanishi J, Takeshima N, Katsumata N, Ushijima K, Kimura T, Takeuchi S, et al. nivolumab versus gemcitabine or pegylated liposomal doxorubicin for patients with platinum-resistant ovarian cancer: open-label, randomized trial in Japan (NINJA). J Clin Oncol. 2021;39:3671–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Contos G, Baca Y, Xiu J, Brown J, Holloway R, Korn WM, et al. Assessment of immune biomarkers and establishing a triple negative phenotype in gynecologic cancers. Gynecol Oncol. 2021;163:312–319.

    Article  CAS  PubMed  Google Scholar 

  18. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.

    Article  PubMed  Google Scholar 

  19. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.

    Article  CAS  PubMed  Google Scholar 

  20. Mandai M, Hamanishi J, Abiko K, Matsumura N, Baba T, Konishi I. Dual faces of IFNγ in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity. Clin Cancer Res. 2016;22:2329–34.

    Article  CAS  PubMed  Google Scholar 

  21. Mimura K, The JL, Okayama H, Shiraishi K, Kua LF, Koh V, et al. PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 2018;109:43–53.

    Article  CAS  PubMed  Google Scholar 

  22. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365–9.

    Article  CAS  PubMed  Google Scholar 

  23. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8.

    Article  CAS  PubMed  Google Scholar 

  24. Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer. 2021;21:298–312.

    Article  CAS  PubMed  Google Scholar 

  25. Mandai M, Hamanishi J, Abiko K, Matsumura N, Baba T, Konishi I. Anti-PD-L1/PD-1 immune therapies in ovarian cancer: basic mechanism and future clinical application. Int J Clin Oncol. 2016;21:456–61.

    Article  CAS  PubMed  Google Scholar 

  26. Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, et al. PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. Clin Cancer Res. 2013;19:1363–74.

    Article  CAS  PubMed  Google Scholar 

  27. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019;18:197–218.

    Article  CAS  PubMed  Google Scholar 

  28. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3:611–8.

    Article  CAS  PubMed  Google Scholar 

  29. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 2007;104:3360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hamanishi J, Mandai M, Abiko K, Matsumura N, Baba T, Yoshioka Y, et al. The comprehensive assessment of local immune status of ovarian cancer by the clustering of multiple immune factors. Clin Immunol. 2011;141:338–47.

    Article  CAS  PubMed  Google Scholar 

  32. Murakami R, Hamanishi J, Brown JB, Abiko K, Yamanoi K, Taki M, et al. Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer. Sci Rep. 2021;11:11427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu JF, Herold C, Gray KP, Penson RT, Horowitz N, Konstantinopoulos PA, et al. Assessment of combined nivolumab and bevacizumab in relapsed ovarian cancer: a Phase 2 Clinical Trial. JAMA Oncol. 2019;5:1731–8.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zamarin D, Burger RA, Sill MW, Powell DJ Jr, Lankes HA, Feldman MD, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG Oncology Study. J Clin Oncol. 2020;38:1814–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Varga A, Piha-Paul S, Ott PA, Mehnert JM, Berton-Rigaud D, Morosky A, et al. Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: analysis of KEYNOTE-028. Gynecol Oncol. 2019;152:243–50.

    Article  CAS  PubMed  Google Scholar 

  36. Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019;30:1080–7.

    Article  CAS  PubMed  Google Scholar 

  37. Lee EK, Xiong N, Cheng SC, Barry WT, Penson RT, Konstantinopoulos PA, et al. Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: a phase 2 clinical trial. Gynecol Oncol. 2020;159:72–78.

    Article  CAS  PubMed  Google Scholar 

  38. Zsiros E, Lynam S, Attwood KM, Wang C, Chilakapati S, Gomez EC, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2021;7:78–85.

    Article  PubMed  Google Scholar 

  39. Walsh CS, Kamrava M, Rogatko A, Kim S, Li A, Cass I, et al. Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer. PLoS ONE. 2021;16:e0252665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liao JB, Gwin WR, Urban RR, Hitchcock-Bernhardt KM, Coveler AL, Higgins DM, et al. Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. J Immunother Cancer. 2021;9:e003122.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Baert T, Ferrero A, Sehouli J, O’Donnell DM, González-Martín A, Joly F, et al. The systemic treatment of recurrent ovarian cancer revisited. Ann Oncol. 2021;32:710–25.

    Article  CAS  PubMed  Google Scholar 

  42. Hamanishi J, Mandai M, Matsumura N, Abiko K, Baba T, Konishi I. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol. 2016;21:462–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sul J, Blumenthal GM, Jiang X, He K, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist. 2016;21:643–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Twomey JD, Zhang B. Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. AAPS J. 2021;23:39.

    Article  PubMed  Google Scholar 

  45. Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019;30:1232–43.

    Article  CAS  PubMed  Google Scholar 

  46. Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, et al. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022;10:e003091.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515:577–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Takamatsu, S, Hamanishi, J, Brown JB, Yamaguchi, K, Yamanoi, K, Murakami, K, et al. Mutation burden-orthogonal tumor genomic subtypes delineate responses to immune checkpoint therapy. J Immunother Cancer. 2022;10:e004831.

  49. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.

    Article  Google Scholar 

  50. Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer. 2015;113:299–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Maio, M, Ascierto, PA, Manzyuk, L, Motola-Kuba, D, Penel, N, Cassier, PA, et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase 2 KEYNOTE-158 Study. Ann Oncol. 2022;S0923-7534(22)01720-3. https://doi.org/10.1016/j.annonc.2022.05.519. Online ahead of print.

  52. Stefania Bellone S, Dana M Roque DM, Eric R Siegel ER, Natalia Buza N, Pei Hui P, Elena Bonazzoli E, et al. A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability. Cancer. 2022;128:1206–18.

    Article  PubMed  Google Scholar 

  53. Ukita M, Hamanishi J, Yoshitomi H, Yamanoi K, Takamatsu S, Ueda A, et al. CXCL13-producing CD4+ T cells accumulate in the early phase of tertiary lymphoid structures in ovarian cancer. JCI Insight. 2022;7:e157215.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Qin M, Hamanishi J, Ukita M, Yamanoi K, Takamatsu S, Abiko K, et al. Tertiary lymphoid structures are associated with favorable survival outcomes in patients with endometrial cancer. Cancer Immunol Immunother. 2022;71:1431–42.

    Article  CAS  PubMed  Google Scholar 

  55. Ferrari N, Ranftl R, Chicherova I, Slaven ND, Moeendarbary E, Farrugia AJ, et al. Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts. Nat Commun. 2019;10:130.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Zhang H, Jiang R, Zhou J, Wang J, Xu Y, Zhang H, et al. CTL attenuation regulated by PS1 in cancer-associated fibroblast. Front Immunol. 2020;11:999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mills AM, Bullock TN, Ring KL. Targeting immune checkpoints in gynecologic cancer: updates & perspectives for pathologists. Mod Pathol. 2022;35:142–51.

    Article  CAS  PubMed  Google Scholar 

  58. Johnston RJ, Su LJ, Pinckney J, Critton D, Boyer E, Krishnakumar A, et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 2019;574:565–70.

    Article  CAS  PubMed  Google Scholar 

  59. Mulati K, Hamanishi J, Matsumura N, Chamoto K, Mise N, Abiko K, et al. VISTA expressed in tumour cells regulates T cell function. Br J Cancer. 2019;120:115–27.

    Article  CAS  PubMed  Google Scholar 

  60. Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol. 2001;2:269–74.

    Article  CAS  PubMed  Google Scholar 

  61. Kimberly A, Hofmeyer KA, Anjana Ray A, Zang X. The contrasting role of B7-H3. Proc Natl Acad Sci USA 2008;105:10277–8.

    Article  Google Scholar 

  62. Miyamoto T, Murakami R, Hamanishi J, Tanigaki K, Hosoe Y, Mise N, et al. B7-H3 suppresses antitumor immunity via the CCL2-CCR2-M2 macrophage axis and contributes to ovarian cancer progression. Cancer Immunol Res. 2022;10:56–69.

    Article  CAS  PubMed  Google Scholar 

  63. Guo Z, Cheng D, Xia Z, Luan M, Wu L, Wang G, et al. Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer. J Transl Med. 2013;11:215.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Chen F, Xu Y, Chen Y, Shan S. TIGIT enhances CD4+ regulatory T‐cell response and mediates immune suppression in a murine ovarian cancer model. Cancer Med. 2020;9:3584–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26:923–37.

    Article  CAS  PubMed  Google Scholar 

  66. Abiko K, Hayashi T, Yamaguchi K, Mandai M, Konishi I. Potential novel ovarian cancer treatment targeting myeloid-derived suppressor cells. Cancer Invest. 2021;39:310–4.

    CAS  PubMed  Google Scholar 

  67. Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013;39:61–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Khalaf K, Hana D, Chou JT-T, Singh C, Mackiewicz A, Kaczmarek M. Aspects of the tumor microenvironment involved in immune resistance and drug resistance. Front Immunol. 2021;27:656364.

    Article  Google Scholar 

  69. Gabrilovich DI, Dmitry I. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5:3–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Horikawa N, Abiko K, Matsumura N, Hamanishi J, Baba T, Yamaguchi K, et al. Expression of vascular endothelial growth factor in ovarian cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells. Clin Can Res. 2017;23:587–99.

    Article  CAS  Google Scholar 

  71. Ai L, Mu S, Wang Y, Wang H, Cai L, Li W, et al. Prognostic role of myeloid-derived suppressor cells in cancers: a systematic review and meta-analysis. BMC Cancer. 2018;18:1220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM, et al. Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin Cancer Res. 2014;20:1601–9.

    Article  CAS  PubMed  Google Scholar 

  73. Horikawa N, Abiko K, Matsumura N, Baba T, Hamanishi J, Yamaguchi K, et al. Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment. Br J Cancer. 2020;122:778–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Gunnar Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.

    Article  CAS  PubMed  Google Scholar 

  75. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Poveda AM, Selle F, Hilpert F, Reuss A, Savarese A, Vergote I, et al. 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. 2015;33:3836–8.

    Article  CAS  PubMed  Google Scholar 

  77. Taki M, Abiko K, Baba T, Hamanishi J, Yamaguchi K, Murakami R, et al. Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation. Nat Commun. 2018;9:1685.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Cormac T. Taylor 1, Eoin P Cummins. The role of NF-κB in hypoxia-induced gene expression. Ann N. Y Acad Sci. 2009;1177:178–84.

    Article  Google Scholar 

  79. Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res. 2015;75:5034–45.

    Article  CAS  PubMed  Google Scholar 

  80. Taki M, Abiko K, Ukita M, Murakami R, Yamanoi K, Yamaguchi K, et al. Tumor immune microenvironment during epithelial-mesenchymal transition. Clin Cancer Res. 2021;27:4669–79.

    Article  CAS  PubMed  Google Scholar 

  81. Binzhi Qian B, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. An Y, Yang Q. Tumor-associated macrophage-targeted therapeutics in ovarian cancer. Int J Cancer. 2021;149:21–30.

    Article  CAS  PubMed  Google Scholar 

  84. Zeng Y, Li B, Liang Y, Reeves PM, Qu X, Ran C, et al. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment. FASEB J. 2019;33:6596–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Moughon DL, He H, Schokrpur S, Jiang ZK, Yaqoob M, David J, et al. Macrophage blockade using CSF1R inhibitors reverses the vascular leakage underlying malignant ascites in late-stage epithelial ovarian cancer. Cancer Res. 2015;75:4742–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Barnett JC, Bean SM, Whitaker RS, Kondoh E, Baba T, Fujii S, et al. Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype. Gynecol Oncol. 2010;116:556–62.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Funding

The authors received no specific funding for this work.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

    Kaoru Abiko

  2. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Junzo Hamanishi & Masaki Mandai

  3. Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka prefecture, Japan

    Noriomi Matsumura

Authors
  1. Kaoru Abiko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junzo Hamanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noriomi Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masaki Mandai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KA drafted the manuscript. JH, NM and MM revised the manuscript. MM supervised the study.

Corresponding author

Correspondence to Kaoru Abiko.

Ethics declarations

Competing interests

JH received grants from Ono Pharmaceutical, Sumitomo Dainippon Pharma, KinoPharma and MSD outside the submitted work. NM is an outside director of Takara Bio Inc. NM received a grant and lecture fees from AstraZeneca and received lecture fees from Takeda Pharmaceutical outside the submitted work. The remaining authors declare no competing interests.

Ethics approval and consent to participate

None.

Consent for publication

None.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abiko, K., Hamanishi, J., Matsumura, N. et al. Dynamic host immunity and PD-L1/PD-1 blockade efficacy: developments after “IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer”. Br J Cancer 128, 461–467 (2023). https://doi.org/10.1038/s41416-022-01960-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-01960-x

This article is cited by

Search

Advanced search

Quick links