title: A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells.
abstract: The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor-specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK (p < 0.0002) and T cell (p = 0.02)-mediated cytotoxicity. Treatment with b-AP15 resulted in increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 expression (p = 0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells (p = 0.006), T cells (p < 0.0001) or b-AP15 alone (p = 0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells (p ≤ 0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anticancer effects of adoptively infused NK and T cells in patients with cancer.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, R8:01, 171 76, Stockholm, Sweden.
authors.forename: Dhifaf
authors.initials: D
authors.lastname: Sarhan
authors.forename: Erik
authors.initials: E
authors.lastname: Wennerberg
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.forename: Deepthy
authors.initials: D
authors.lastname: Gurajada
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundqvist
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D016219:Immunotherapy, Adoptive; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010881:Piperidones / Q000276:immunology* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000276:immunology* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C569633:3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one; D016207:Cytokines; D010881:Piperidones; D011480:Protease Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D046988:Proteasome Endopeptidase Complex