Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer
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The programmed death-1 (PD-1) pathway is important in the maintenance of peripheral tolerance and homeostasis through suppression of T cell receptor signaling. As such, it is employed by many tumors as a means of immune escape. We have investigated the role of this pathway in human ovarian cancer (OC) to assess its potential role as a diagnostic and/or prognostic marker and therapeutic target, following recent clinical trial success of antibody therapy directed at this pathway. We show programmed death ligand-1 (PD-L1) expression on monocytes in the ascites and blood of patients with malignant OC is strikingly higher than those with benign/borderline disease, with no overlap in the values between these groups. We characterize the regulation of this molecule and show a role of IL-10 present in ascitic fluid. Flow cytometric analysis of T cells present in the ascites and blood showed a correlation of PD-1 expression with malignant tumors versus benign/borderline, in a similar manner to PD-L1 expression on monocytes. Finally, we demonstrate functional links between PD-L1 expression on monocytes and OC tumor cells with suppression of T cell responses. Overall, we present data based on samples obtained from women with ovarian cancer, suggesting the PD-1 pathway may be used as a reliable diagnostic marker in OC, as well as a viable target for use with PD-1/PD-L1-directed antibody immunotherapy.
KeywordsOvarian cancer PD-L1 Monocytes B7-H1 Immune regulation IL-10
We wish to thank the clinical staff at Queen Charlotte’s hospital to their contribution to patient recruitment. Sadaf Ghaem-Maghami received funding from Rosie Williams Charitable Trust and Mann-Hodgson Trust for this work. Nor Haslinda Abdul Aziz was supported by a studentship from Malaysian Ministry of Education. Christian J. Maine was supported by an MRC studentship. Claudia Hayford was supported by Ovarian Cancer Action. Support was also provided by the Experimental Cancer Medicine Centre at Imperial College London and by the National Institute for Health Research (NIHR) Biomedical Research Centre and Ovarian Cancer Action Centre based at Imperial College London.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, Bauknecht T, Richter B, Warm M, Schroder W, Olbricht S, Nitz U, Jackisch C, Emons G, Wagner U, Kuhn W, Pfisterer J (2003) A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95(17):1320–1329PubMedCrossRefGoogle Scholar
- 4.Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R (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. J Clin Oncol 21(17):3194–3200. doi: 10.1200/JCO.2003.02.153 PubMedCrossRefGoogle Scholar
- 5.Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213. doi: 10.1056/NEJMoa020177 PubMedCrossRefGoogle Scholar
- 8.Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034PubMedCentralPubMedCrossRefGoogle Scholar
- 9.Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y (2005) Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 11(8):2947–2953. doi: 10.1158/1078-0432.CCR-04-1469 PubMedCrossRefGoogle Scholar
- 10.Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, Zincke H, Blute ML, Strome SE, Leibovich BC, Kwon ED (2004) Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 101(49):17174–17179. doi: 10.1073/pnas.0406351101 PubMedCrossRefGoogle Scholar
- 12.Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (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):3360–3365. doi: 10.1073/pnas.0611533104 PubMedCrossRefGoogle Scholar
- 13.Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, Yamaguchi K, Murakami R, Yamamoto A, Kharma B, Kosaka K, Konishi I (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):1363–1374. doi: 10.1158/1078-0432.CCR-12-2199 PubMedCrossRefGoogle Scholar
- 14.Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O, Burow M, Gordon A, Dhurandhar N, Myers L, Berggren R, Hemminki A, Alvarez RD, Emilie D, Curiel DT, Chen L, Zou W (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9(5):562–567. doi: 10.1038/nm863 PubMedCrossRefGoogle Scholar
- 15.Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. doi: 10.1056/NEJMoa1200694 PubMedCentralPubMedCrossRefGoogle Scholar
- 16.Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi: 10.1056/NEJMoa1200690 PubMedCentralPubMedCrossRefGoogle Scholar
- 18.Geng L, Jiang G, Fang Y, Dong S, Xie H, Chen Y, Shen M, Zheng S (2006) B7-H1 expression is upregulated in peripheral blood CD14 + monocytes of patients with chronic hepatitis B virus infection, which correlates with higher serum IL-10 levels. J Viral Hepat 13(11):725–733. doi: 10.1111/j.1365-2893.2006.00746.x PubMedCrossRefGoogle Scholar
- 19.Trabattoni D, Saresella M, Biasin M, Boasso A, Piacentini L, Ferrante P, Dong H, Maserati R, Shearer GM, Chen L, Clerici M (2003) B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression. Blood 101(7):2514–2520. doi: 10.1182/blood-2002-10-3065 PubMedCrossRefGoogle Scholar
- 20.Krempski J, Karyampudi L, Behrens MD, Erskine CL, Hartmann L, Dong H, Goode EL, Kalli KR, Knutson KL (2011) Tumor-infiltrating programmed death receptor-1 + dendritic cells mediate immune suppression in ovarian cancer. J Immunol 186(12):6905–6913. doi: 10.4049/jimmunol.1100274 PubMedCentralPubMedCrossRefGoogle Scholar