A review of the PD-1/PD-l1 checkpoint in bladder cancer: from mediator of immune escape to target for treatment

Cover Page


Treatment of bladder cancer has evolved over time to include the traditional modalities of chemotherapy and surgery, and it has been greatly impacted by the use of immunotherapy. Modern immunotherapy focuses on checkpoint protein inhibitors, which are molecules impeding immune function, thereby allowing unregulated tumor cell growth and proliferation. Several immune checkpoint targets (programmed death ligand-1 [PD-L1], programmed cell death protein-1 [PD-1], and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]) have received the most attention in the treatment of bladder cancer, whereas inhibitor agents have either been approved or are in late-stage development. This review describes the most recent data on PD-L1-inhibiting agents, found on the surface of tumor cells, and PD-1, found on activated T and B cells and macrophages. Aim. A review of modern PD-1 and PD-L1 inhibitors as target immunotherapeutic agents for the treatment of bladder cancer.

Materials and methods. We performed a comprehensive literature review using MEDLINE/PubMed and EMBASE.

Results. The PD-1/PD-L1 pathway is possibly manipulated by cancer cells to suppress the immune system. PD-1/PD-L1 blockade has been tested in clinical trials for various malignancies, including metastatic urothelial carcinoma, with significant response rates and limited adverse effects. PD-L1 expression has mixed results as a prognostic marker for bladder cancer.

Conclusions. PD-1 is a key receptor mediating immune escape, and agents targeting its ligand, PD-L1, have already been successful in patients with metastatic urothelial cancer. Further research is warranted to standardize the criteria for PD-L1 positivity and to optimize its use in the treatment of bladder cancer.

Andrey I. Gorelov

St. Petersburg State University

Author for correspondence.
Email: gorelov_a_i@mail.ru

Russian Federation, Saint Petersburg

Doctor of Medical Science, Professor, Department of Hospital Surgery

Andrei S. Simbirtsev

Institute of Highly Pure Biopreparations, FMBA of Russia

Email: gorelov_a_i@mail.ru

Russian Federation, Saint Petersburg

Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Scientific Supervisor

Dmitrii A. Zhuravskii

St. Petersburg State University

Email: zhuravskiy.spbu@gmail.com

Russian Federation, Saint Petersburg


Anna A. Gorelova

Saint Petersburg State Research Institute of Phthisiopulmonology

Email: gorelov_a_i@mail.ru

Russian Federation, Saint Petersburg


  1. Sylvester RJ, van der MA, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002;168:1964-1970. doi: 10.1097/00005392-200211000-00016.
  2. Starnes CO. Coley’s toxins in perspective. Nature 1992; 357(6373):11-12. doi: 10.1038/360023b0.
  3. Pearl R. Cancer and tuberculosis. Am J Epidem. 1929;9(1):97-159. doi: 10.1093/oxfordjournals.aje.a121646.
  4. Old LJ, Clarke, DA, Benacerraf B. Effect of Bacillus Calmette-Guérin Infection on Transplanted Tumours in the Mouse. Nature. 1959;184(4682):291-292. doi: 10.1038/184291a0.
  5. Baker M, Taub R. BCG in malignant melanoma. Lancet. 1973; 301(7812):1117-1118. doi: 10.1016/s0140-6736(73)90423-6.
  6. Herr HW, Morales A. History of Bacillus Calmette-Guerin and Bladder Cancer: An Immunotherapy Success Story. J Urol. 2008;179(1),53-56. doi: 10.1016/j.juro.2007.08.122.
  7. Malmström P, Sylvester R. POD-7.08: Intravesical Mitomycin C Versus Bacillus Calmette-Guérin for Non-muscle Invasive Bladder Cancer: An Individual Patient Data Meta-analysis of Randomized Studies. Urology. 2008;72(5):S57. doi: 10.1016/j.urology.2008.08.161.
  8. Weishaupt C, Munoz KN, Buzney E, et al. T-Cell Distribution and Adhesion Receptor Expression in Metastatic Melanoma. Clinical Cancer Research. 2007;13(9): 2549-2556. doi: 10.1158/1078-0432.ccr-06-2450.
  9. Medema JP, de Jong J, Peltenburg LTC, et al. Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proceedings of the National Academy of Sciences. 2001;98(20):11515-11520. doi: 10.1073/pnas.201398198.
  10. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncology. 2010;11(2):155-164. doi: 10.1016/s1470-2045(09)70334-1.
  11. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer. 2012;12(4):252-264. doi: 10.1038/nrc3239.
  12. Keir ME, Butte MJ, Freeman G, et al. PD-1 and its Ligands in Tolerance and Immunity. Annual Review of Immunology. 2008;26(1):677-704. doi: 10.1146/annurev.immunol.26.021607.090331.
  13. Shibahara K, Asano M, Ishida Y, et al. Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death. Gene. 1995;166(2):297-301. doi: 10.1016/0378-1119(95)00607-9.
  14. Boussiotis VA, Chatterjee P, Li L. Biochemical Signaling of PD-1 on T Cells and Its Functional Implications. The Cancer Journal. 2014;20(4):265-271. doi: 10.1097/ppo.0000000000000059.
  15. Francisco L, Salinas V, Brown K, et al. PD-L1 Regulates the Development, Maintenance and Function of Induced-regulatory T Cells. Clinical Immunology. 2009;131,S45. doi: 10.1016/j.clim.2009.03.126.
  16. Ohaegbulam KC, Assal A, Lazar-Molnar E, et al. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends in Molecular Medicine. 2015;21(1):24-33. doi: 10.1016/j.molmed.2014.10.009.
  17. Zhou TC, Sankin AI, Porcelli SA, et al. A review of the PD-1/PD-L1 checkpoint in bladder cancer: From mediator of immune escape to target for treatment Urologic Oncology: Seminars and Original Investigations. 2017;35(1):14-20. doi: 10.1016/j.urolonc.2016.10.004.
  18. Boorjian SA, Sheinin Y, Crispen PL, et al. T-Cell Coregulatory Molecule Expression in Urothelial Cell Carcinoma: Clinicopathologic Correlations and Association with Survival. Clinical Cancer Research. 2008;14(15),4800-4808. doi: 10.1158/1078-0432.ccr-08-0731.
  19. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata. Cancer. 2007;109(8):1499-1505. doi: 10.1002/cncr.22588.
  20. Zibelman M, Ramamurthy C, Plimack ER Emerging role of immunotherapy in urothelial carcinoma - Advanced disease. Urologic Oncology: Seminars and Original Investigations. 2016;34(12):538-547. doi: 10.1016/j.urolonc.2016.10.017.
  21. Bellmunt J, Petrylak DP, Powles T, et al. Inhibition of PD-L1 by mpdl3280a leads to clinical activity in pts with metastatic urothelial bladder cancer (UBC). Annals of Oncology. 2014;25(Suppl.4):iv280. doi: 10.1093/annonc/mdu337.1.
  22. Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treatment Reviews. 2017;54:58-67. doi: 10.1016/j.ctrv.2017.01.007.
  23. Mann JE Atezolizumab (Tecentriq®). Oncology Times. 2017;39(4):31. doi: 10.1097/01.cot.0000513325.52233.f1.
  24. Loriot Y, Rosenberg JE, Powles TB, et al. Atezolizumab (atezo) in platinum (plat)-treated locally advanced/metastatic urothelial carcinoma (mUC): Updated OS, safety and biomarkers from the Ph II IMvigor210 study. Annals of Oncology. 2016;27(Suppl.6): doi: 10.1093/annonc/mdw373.11.
  25. Rosenberg J, Petrylak D, Abidoye O, et al. Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal multicenter phase II study (IMvigor 210). European Journal of Cancer. 2015;51:S720. doi: 10.1016/s0959-8049(16)31942-6.
  26. Sonpavde G, Sternberg CN, Rosenberg JE, et al. Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium. The Lancet Oncology. 2010;11(9):861-870. doi: 10.1016/s1470-2045(10)70086-3.
  27. Daskivich TJ, Belldegrun A. Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. European Urology. 2015;67(4):816-817. doi: 10.1016/j.eururo.2014.12.052.
  28. Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. The Lancet Oncology. 2016;17(11):1590-1598. doi: 10.1016/s1470-2045(16)30496-x.
  29. Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate 275 study. Annals of Oncology. 2016;27 (suppl.6). doi: 10.1093/annonc/mdw435.24.
  30. Hamid O, Robert C, Daud A, et al. Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma. New England Journal of Medicine. 2013;369(2):134-44. doi: 10.1056/nejmoa1305133.
  31. Plimack ER, Gupta S, Bellmunt J, et al. Phase 1b study of pembrolizumab (pembro;mk-3475) in patients (RTS) with advanced urothelial tract cancer. Annals of Oncology. 2014;25(Suppl.4). doi: 10.1093/annonc/mdu438.24.
  32. O’Donnell PH, Plimack ER, Bellmunt J, et al. Pembrolizumab (Pembro;MK-3475) for advanced urothelial cancer: Results of a phase IB study. Journal of Clinical Oncology. 2015;33(Suppl.7): 296-296. doi: 10.1200/jco.2015.33.7_suppl.296.
  33. Gupta S, O’Donnell P, Plimack ER, et al. A phase 1b study of pembrolizumab (Pembro;MK-3475) for advanced urothelial cancer. The Journal of Urology. 2015;193(4):e861-e862. doi: 10.1016/j.juro.2015.02.2473.
  34. Necchi A, Bellmunt J, De Wit R, et al. Pembrolizumab vs investigator-choice chemotherapy for previously treated advanced urothelial cancer: Phase 3 KEYNOTE-045 study. European Journal of Cancer. 2017;72:S2. doi: 10.1016/s0959-8049(17)30092-8.
  35. Thompson RH, Leibovich BC, Dong H, et al. Tumor B7-H1 is Associated with Poor Prognosis in Renal Cell Carcinoma Patients with Long Term Follow-Up. The Journal of Urology. 2006;175(4):126. doi: 10.1016/s0022-5347(18)32642-9.
  36. Tang F, Zheng P. Tumor cells versus host immune cells: whose PD-L1 contributes to PD-1/PD-L1 blockade mediated cancer immunotherapy? Cell & Bioscience. 2018;8(1). doi: 10.1186/s13578-018-0232-4.
  37. Faraj SF, Munari E, Guner G, et al. Assessment of Tumoral PD-L1 Expression and Intratumoral CD8+ T Cells in Urothelial Carcinoma. Urology. 2015;85(3):703.e1-703.e6. doi: 10.1016/j.urology.2014.10.020.
  38. Bellmunt J, Mullane SA, Werner L, et al. Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Annals of Oncology. 2015;26(4):812-817. doi: 10.1093/annonc/mdv009.
  39. Nakanishi J, Wada Y, Matsumoto K, et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunology, Immunotherapy. 2006;56(8):1173-1182. doi: 10.1007/s00262-006-0266-z.
  40. Wang Y, Zhuang Q, Zhou S, et al. Costimulatory molecule B7-H1 on the immune escape of bladder cancer and its clinical significance. Journal of Huazhong University of Science and Technology [Medical Sciences], 2009;29(1):77-79. doi: 10.1007/s11596-009-0116-2.
  41. Prestayko AW, D’Aoust JC, Issell BF, et al. Cisplatin (cis-diamminedichloroplatinum II). Cancer Treatment Reviews. 1979;6(1): 17-39. doi: 10.1016/s0305-7372(79)80057-2.


Abstract - 365

PDF (Russian) - 172


Copyright (c) 2018 Gorelov A.I., Simbirtsev A.S., Zhuravskii D.A., Gorelova A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.