title: Doxorubicin sensitizes human tumor cells to NK cell- and T-cell-mediated killing by augmented TRAIL receptor signaling.
abstract: Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat different types of malignancy. In this study, it was studied whether DOX could be used to render tumor cells susceptible to apoptosis by NK and T cells. Pretreatment with subapoptotic doses of DOX sensitized tumor cell lines of various histotypes to both NK and T cells resulting in a 3.7 to 32.7% increase in lysis (2.5 mean fold increase, p < 0.0001) and a 2.9 to 14.2% increase in lysis (3.0 mean-fold increase, p < 0.05), respectively. The sensitizing effect of the drug was primarily dependent on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptor signaling, but not on Fas-ligand, perforin, NKG2D or DNAM-1. The central role of the TRAIL signaling pathway was further supported by an increased expression of TRAIL-R2 on DOX-treated tumor cells and by downregulation of cellular FLICE inhibitory protein, the inhibitors of death receptor-mediated apoptosis. Compared to untreated cells, pretreatment of tumor cells with DOX showed increased processing and activation of caspase-8 on coculture with NK or T cells. The significance of this treatment strategy was confirmed using a xenogeneic tumor-bearing mouse model. Tumor progression was delayed in mice that received either NK cells (p < 0.05) or T cells (p < 0.0001) following DOX treatment compared to mice receiving either cell type alone. Moreover, combined infusion of both NK and T cells following DOX treatment not only delayed tumor progression but also significantly improved the long-term survival (p < 0.01). Based on these findings, it was proposed that DOX can be used to improve the efficacy of adoptive cell therapy in patients with cancer.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Wennerberg
authors.forename: Dhifaf
authors.initials: D
authors.lastname: Sarhan
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlsten
authors.forename: Vitaliy O
authors.initials: VO
authors.lastname: Kaminskyy
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundqvist
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology*; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D054353:Perforin / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000903:Antibiotics, Antineoplastic; D000945:Antigens, Differentiation, T-Lymphocyte; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D000098862:T Lineage-Specific Activation Antigen 1; D053222:Fas Ligand Protein; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D054353:Perforin; D004317:Doxorubicin; D053181:Caspase 8
keywords: adoptive cell therapy; doxorubicin; natural killer cells; tumor-infiltrating lymphocytes