title: Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.
abstract: 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.
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Shawn T
authors.initials: ST
authors.lastname: Beug
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Beauregard
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Cristin
authors.initials: C
authors.lastname: Healy
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Tarun
authors.initials: T
authors.lastname: Sanda
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
authors.forename: Martine
authors.initials: M
authors.lastname: St-Jean
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
authors.forename: Janelle
authors.initials: J
authors.lastname: Chabot
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Walker
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
authors.forename: Aditya
authors.initials: A
authors.lastname: Mohan
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Earl
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Senger
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Robbins
authors.affiliation: Institute of Virology, University Medical Center Freiburg, Freiburg D-79104, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
authors.affiliation: H. Lee Moffit Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
authors.forename: Eric C
authors.initials: EC
authors.lastname: LaCasse
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Korneluk
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000276:immunology; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007156:Immunologic Memory; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D015398:Signal Transduction; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D018116:Vesiculovirus / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C107521:Birc4 protein, mouse; C498919:Cd274 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D016898:Interferon-alpha; C574246:LCL161; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D011070:Poly I-C