title: IAP inhibitors enhance co-stimulation to promote tumor immunity.
abstract: The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell-dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.
authors.affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Dougan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dougan
authors.forename: Joanna
authors.initials: J
authors.lastname: Slisz
authors.forename: Brant
authors.initials: B
authors.lastname: Firestone
authors.forename: Matthew
authors.initials: M
authors.lastname: Vanneman
authors.forename: Dobrin
authors.initials: D
authors.lastname: Draganov
authors.forename: Girija
authors.initials: G
authors.lastname: Goyal
authors.forename: Weibo
authors.initials: W
authors.lastname: Li
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Richard
authors.initials: R
authors.lastname: Blumberg
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Dale
authors.initials: D
authors.lastname: Porter
authors.forename: Leigh
authors.initials: L
authors.lastname: Zawel
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines; D006801:Humans; D056747:Immunomodulation; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha