title: The proteasome inhibitor bortezomib sensitizes melanoma cells toward adoptive CTL attack.
abstract: Adoptive transfer of tumor-specific cytolytic T lymphocytes (CTL) results in target cell lysis by activating the intrinsic apoptotic cell death program. Not surprisingly, deregulation of the apoptotic machinery is one of the central mechanisms by which tumor cells escape immune destruction despite specific CTL recognition. Here we show that treatment with the proteasome inhibitor bortezomib sensitizes previously resistant tumor cells for cytolytic T-cell attack. Human T cells were redirected toward melanoma cells by engineered expression of an immunoreceptor with binding specificity for high molecular weight-melanoma-associated antigen. Established melanoma cell lines as well as primary melanoma cells from tumor biopsies, which are notoriously resistant toward T-cell lysis, became sensitive upon bortezomib treatment. Detailed analysis of the underlying molecular mechanism revealed that bortezomib treatment induced mitochondrial accumulation of NOXA, which potentiated the release of mitochondrial second mitochondria-derived activator of caspase (SMAC) in response to CTL effector functions, including caspase-8 and granzyme B. Our data indicate that proteasome inhibition increases the sensitivity of tumor cells toward cytolytic T-cell attack by NOXA-mediated enhancement of mitochondrial SMAC release.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Seeger
authors.forename: Patrick
authors.initials: P
authors.lastname: Schmidt
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brinkmann
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Hombach
authors.forename: Oliver
authors.initials: O
authors.lastname: Coutelle
authors.forename: Paola
authors.initials: P
authors.lastname: Zigrino
authors.forename: Diana
authors.initials: D
authors.lastname: Wagner-Stippich
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
mesh_terms: D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004789:Enzyme Activation; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C498702:PMAIP1 protein, human; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C065686:carcinoembryonic antigen binding protein, human; D000069286:Bortezomib; D053804:Granzymes; C505530:CASP8 protein, human; D053181:Caspase 8