title: Poly(I:C) potentiates Bacillus Calmette-Guérin immunotherapy for bladder cancer.
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.
authors.affiliation: 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.
authors.forename: Cherifa
authors.initials: C
authors.lastname: Ayari
authors.affiliation: 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.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Besançon
authors.affiliation: 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.
authors.forename: Alain
authors.initials: A
authors.lastname: Bergeron
authors.affiliation: 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. helene.larue@crhdq.ulaval.ca.
authors.forename: Hélène
authors.initials: H
authors.lastname: LaRue
authors.affiliation: 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.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bussières
authors.affiliation: 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.
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D018836:Inflammation Mediators; D011070:Poly I-C
keywords: BCG; Bladder cancer; Immunotherapy; Mouse model; Poly(I:C); TLR