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Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.
Beug, Shawn T; Beauregard, Caroline E; Healy, Cristin; Sanda, Tarun; St-Jean, Martine; Chabot, Janelle; Walker, Danielle E; Mohan, Aditya; Earl, Nathalie; Lun, Xueqing; Senger, Donna L; Robbins, Stephen M; Staeheli, Peter; Forsyth, Peter A; Alain, Tommy; LaCasse, Eric C; Korneluk, Robert G.
Afiliación
  • Beug ST; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Beauregard CE; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
  • Healy C; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Sanda T; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
  • St-Jean M; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Chabot J; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
  • Walker DE; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Mohan A; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
  • Earl N; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Lun X; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Senger DL; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Robbins SM; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Staeheli P; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • Forsyth PA; Arnie Charbonneau Cancer Institute, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
  • Alain T; Arnie Charbonneau Cancer Institute, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
  • LaCasse EC; Arnie Charbonneau Cancer Institute, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
  • Korneluk RG; Institute of Virology, University Medical Center Freiburg, Freiburg D-79104, Germany.
Nat Commun ; 82017 02 15.
Article en En | MEDLINE | ID: mdl-28198370
Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles / Neoplasias Encefálicas / Interferón beta / Interferón-alfa / Glioblastoma / Antineoplásicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2017 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles / Neoplasias Encefálicas / Interferón beta / Interferón-alfa / Glioblastoma / Antineoplásicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2017 Tipo del documento: Article Pais de publicación: Reino Unido