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Poly(I:C) potentiates Bacillus Calmette–Guérin immunotherapy for bladder cancer

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Abstract

Non-specific immunotherapy consisting of intravesical instillation of Bacillus Calmette–Guérin (BCG) is currently the best available treatment to prevent non-muscle-invasive bladder tumor recurrence and progression. This treatment however is suboptimal, and more effective immunotherapeutic approaches are needed. Toll-like receptors (TLRs) play a major role in the activation of the immune system in response to pathogens and danger signals but also in anti-tumor responses. We previously showed that human urothelial cells express functional TLRs and respond to TLR2 and TLR3 agonists. In this study, we analyzed the potential of polyinosinic:polycytidylic acid [poly(I:C)], a TLR3 agonist, to replace or complement BCG in the treatment of non-muscle-invasive bladder cancer. We observed that poly(I:C) had an anti-proliferative, cytotoxic, and apoptotic effect in vitro on two low-grade human bladder cancer cell lines, MGH-U3 and RT4. In MGH-U3 cells, poly(I:C) induced growth arrest at the G1-S transition. Poly(I:C) also increased the immunogenicity of MGH-U3 and RT4 cells, inducing the secretion of MHC class I molecules and of pro-inflammatory cytokines. By comparison, poly(I:C) had less in vitro impact on two high-grade human bladder cancer cell lines, 5637 and T24, and on MBT-2 murine high-grade bladder cancer cells. The latter can be used as an immunocompetent model of bladder cancer. The combination poly(I:C)/BCG was much more effective in reducing MBT-2 tumor growth in mice than either treatment alone. It completely cured 29 % of mice and also induced an immunological memory response. In conclusion, our study suggests that adding poly(I:C) to BCG may enhance the therapeutic effect of BCG.

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Abbreviations

BCG:

Bacillus Calmette–Guérin

LDH:

Lactate dehydrogenase

NMIBC:

Non-muscle-invasive bladder cancer

PKR:

Double-stranded RNA-activated protein kinase

poly(I:C):

Polyinosinic:polycytidylic acid

TLR:

Toll-like receptor

Treg:

Regulatory T cell

UCs:

Urothelial cells

References

  1. Brausi M, Witjes JA, Lamm D, Persad R, Palou J, Colombel M, Buckley R, Soloway M, Akaza H, Bohle A (2011) A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J Urol 186:2158–2167

    Article  PubMed  Google Scholar 

  2. Brandau S, Suttmann H (2007) Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement. Biomed Pharmacother 61:299–305

    Article  CAS  PubMed  Google Scholar 

  3. Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, Comperat E, Sylvester RJ, Kaasinen E, Bohle A, Palou RJ, Roupret M (2013) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 64:639–653

    Article  PubMed  Google Scholar 

  4. Yates DR, Roupret M (2011) Contemporary management of patients with high-risk non-muscle-invasive bladder cancer who fail intravesical BCG therapy. World J Urol 29:415–422

    Article  CAS  PubMed  Google Scholar 

  5. Nicodemus CF, Berek JS (2010) TLR3 agonists as immunotherapeutic agents. Immunotherapy 2:137–140

    Article  CAS  PubMed  Google Scholar 

  6. Vacchelli E, Eggermont A, Sautes-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L (2013) Trial watch: toll-like receptor agonists for cancer therapy. Oncoimmunology 2:e25238

    Article  PubMed Central  PubMed  Google Scholar 

  7. Vacchelli E, Galluzzi L, Eggermont A, Fridman WH, Galon J, Sautes-Fridman C, Tartour E, Zitvogel L, Kroemer G (2012) Trial watch: FDA-approved toll-like receptor agonists for cancer therapy. Oncoimmunology 1:894–907

    Article  PubMed Central  PubMed  Google Scholar 

  8. LaRue H, Ayari C, Bergeron A, Fradet Y (2013) Toll-like receptors in urothelial cells–targets for cancer immunotherapy. Nat Rev Urol 10:537–545

    PubMed  Google Scholar 

  9. Makkouk A, Abdelnoor AM (2009) The potential use of toll-like receptor (TLR) agonists and antagonists as prophylactic and/or therapeutic agents. Immunopharmacol Immunotoxicol 31:331–338

    Article  CAS  PubMed  Google Scholar 

  10. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11:373–384

    Article  CAS  PubMed  Google Scholar 

  11. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650

    Article  CAS  PubMed  Google Scholar 

  12. Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176:4894–4901

    Article  CAS  PubMed  Google Scholar 

  13. Paone A, Starace D, Galli R, Padula F, De CP, Filippini A, Ziparo E, Riccioli A (2008) Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis 29:1334–1342

    Article  CAS  PubMed  Google Scholar 

  14. Apodaca G (2004) The uroepithelium: not just a passive barrier. Traffic 5:117–128

    Article  CAS  PubMed  Google Scholar 

  15. Bevers RF, Kurth KH, Schamhart DH (2004) Role of urothelial cells in BCG immunotherapy for superficial bladder cancer. Br J Cancer 91:607–612

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Ayari C, Bergeron A, LaRue H, Menard C, Fradet Y (2011) Toll-like receptors in normal and malignant human bladders. J Urol 185:1915–1921

    Article  CAS  PubMed  Google Scholar 

  17. Kuznik A, Bencina M, Svajger U, Jeras M, Rozman B, Jerala R (2011) Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol 186:4794–4804

    Article  CAS  PubMed  Google Scholar 

  18. Huang JT, Schneider RJ (1990) Adenovirus inhibition of cellular protein synthesis is prevented by the drug 2-aminopurine. Proc Natl Acad Sci USA 87:7115–7119

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Picard V, Bergeron A, LaRue H, Fradet Y (2007) MAGE-A9 mRNA and protein expression in bladder cancer. Int J Cancer 120:2170–2177

    Article  CAS  PubMed  Google Scholar 

  20. LaRue H, Parent-Vaugeois C, Bergeron A, Champetier S, Fradet Y (1997) Influence of spatial configuration on the expression of carcinoembryonic antigen and mucin antigens in human bladder cancer. Int J Cancer 71:986–992

    Article  CAS  PubMed  Google Scholar 

  21. Fisher RP (2012) The CDK network: linking cycles of cell division and gene expression. Genes Cancer 3:731–738

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811

    Article  CAS  PubMed  Google Scholar 

  23. Sanchez AM, Zhu J, Huang X, Yang Y (2012) The development and function of memory regulatory T cells after acute viral infections. J Immunol 189:2805–2814

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Hasan UA, Caux C, Perrot I, Doffin AC, Menetrier-Caux C, Trinchieri G, Tommasino M, Vlach J (2007) Cell proliferation and survival induced by toll-like receptors is antagonized by type I IFNs. Proc Natl Acad Sci USA 104:8047–8052

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Salaun B, Lebecque S, Matikainen S, Rimoldi D, Romero P (2007) Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res 13:4565–4574

    Article  CAS  PubMed  Google Scholar 

  26. Brierley MM, Fish EN (2002) Review: IFN-alpha/beta receptor interactions to biologic outcomes: understanding the circuitry. J Interferon Cytokine Res 22:835–845

    Article  CAS  PubMed  Google Scholar 

  27. Smith EB, Schwartz M, Kawamoto H, You X, Hwang D, Liu H, Scherr DS (2007) Antitumor effects of imidazoquinolines in urothelial cell carcinoma of the bladder. J Urol 177:2347–2351

    Article  CAS  PubMed  Google Scholar 

  28. Filion MC, Lepicier P, Morales A, Phillips NC (1999) Mycobacterium phlei cell wall complex directly induces apoptosis in human bladder cancer cells. Br J Cancer 79:229–235

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Matsumoto M, Seya T (2008) TLR3: interferon induction by double-stranded RNA including poly(I:C). Adv Drug Deliv Rev 60:805–812

    Article  CAS  PubMed  Google Scholar 

  30. Yang I, Kremen TJ, Giovannone AJ, Paik E, Odesa SK, Prins RM, Liau LM (2004) Modulation of major histocompatibility complex class I molecules and major histocompatibility complex-bound immunogenic peptides induced by interferon-alpha and interferon-gamma treatment of human glioblastoma multiforme. J Neurosurg 100:310–319

    Article  CAS  PubMed  Google Scholar 

  31. Ninalga C, Loskog A, Klevenfeldt M, Essand M, Totterman TH (2005) CpG oligonucleotide therapy cures subcutaneous and orthotopic tumors and evokes protective immunity in murine bladder cancer. J Immunother 28:20–27

    Article  PubMed  Google Scholar 

  32. Perret R, Sierro SR, Botelho NK, Corgnac S, Donda A, Romero P (2013) Adjuvants that improve the ratio of antigen-specific effector to regulatory T cells enhance tumor immunity. Cancer Res 73:6597–65608

    Article  CAS  PubMed  Google Scholar 

  33. Morales A, Pang AS (1986) Prophylaxis and therapy of an experimental bladder cancer with biological response modifiers. J Urol 135:191–193

    CAS  PubMed  Google Scholar 

  34. Morales A, Pang AS (1986) Experimental immunotherapy with NK-like cells. A preliminary report. Cancer Immunol Immunother 21:156–160

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Grants from the Canadian Institutes of Health Research (Grant # MOP93541) and from the Canadian Cancer Society Research Institute (Grant No. 701601).

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Authors and Affiliations

  1. Centre de recherche sur le cancer de l’Université Laval, Centre de recherche du CHU de Québec-Université Laval, L’Hôtel-Dieu de Québec, 10 McMahon, Québec, G1R 3S1, Canada

    Cherifa Ayari, Marjorie Besançon, Alain Bergeron, Hélène LaRue, Vanessa Bussières & Yves Fradet

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  1. Cherifa Ayari
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  2. Marjorie Besançon
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  3. Alain Bergeron
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  4. Hélène LaRue
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Correspondence to Hélène LaRue.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of our institution.

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Ayari, C., Besançon, M., Bergeron, A. et al. Poly(I:C) potentiates Bacillus Calmette–Guérin immunotherapy for bladder cancer. Cancer Immunol Immunother 65, 223–234 (2016). https://doi.org/10.1007/s00262-015-1789-y

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  • DOI: https://doi.org/10.1007/s00262-015-1789-y

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