title: Proinflammatory characteristics of SMAC/DIABLO-induced cell death in antitumor therapy.
abstract: Molecular mimetics of the caspase activator second mitochondria-derived activator of caspase (SMAC) are being investigated for use in cancer therapy, but an understanding of in vivo effects remains incomplete. In this study, we offer evidence that SMAC mimetics elicit a proinflammatory cell death in cancer cells that engages an adaptive antitumor immune response. Cancer cells of different histologic origin underwent apoptosis when transduced with lentiviral vectors encoding a cytosolic form of the SMAC mimetic LV-tSMAC. Strikingly, treatment of tumor-bearing mice with LV-tSMAC resulted in the induction of apoptosis, activation of antitumor immunity, and enhanced survival. Antitumor immunity was accompanied by an increase of tumor-infiltrating lymphocytes displaying low PD-1 expression, high lytic capacity, and high levels of IFN-γ when stimulated. We also noted in vivo a decrease in regulatory T cells along with in vitro activation of tumor-specific CD8(+) T cells by dendritic cells (DC) isolated from tumor draining lymph nodes. Last, tumor-specific cytotoxic T cells were also found to be activated in vivo. Mechanistic analyses showed that transduction of cancer cells with LV-tSMAC resulted in exposure of calreticulin but not release of HMGB1 or ATP. Nevertheless, DCs were activated upon engulfment of dying cancer cells. Further validation of these findings was obtained by their extension in a model of human melanoma using transcriptionally targeted LV-tSMAC. Together, our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer.
authors.affiliation: Department of Immunology-Physiology, Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Jette, Belgium.
authors.forename: Perpetua U
authors.initials: PU
authors.lastname: Emeagi
authors.forename: Sandra
authors.initials: S
authors.lastname: Van Lint
authors.forename: Cleo
authors.initials: C
authors.lastname: Goyvaerts
authors.forename: Sarah
authors.initials: S
authors.lastname: Maenhout
authors.forename: Anje
authors.initials: A
authors.lastname: Cauwels
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
authors.forename: Tomas
authors.initials: T
authors.lastname: Bos
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Joeri L
authors.initials: JL
authors.lastname: Aerts
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D040761:Biomimetic Materials / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D037282:Calreticulin / Q000032:analysis; D016923:Cell Death; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D016086:Lentivirus; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D024101:Mitochondrial Proteins / Q000235:genetics*; D009369:Neoplasms / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; D037282:Calreticulin; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins