title: Bortezomib enhances expression of effector molecules in anti-tumor CD8+ T lymphocytes by promoting Notch-nuclear factor-κB crosstalk.
abstract: The immunosuppressive tumor microenvironment usurps host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various metazoan cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with the proteasome inhibitor bortezomib in mice bearing various solid tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues, thereby increasing CD8+T-lymphocyte IFNγ secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Bortezomib also neutralized TGFβ-mediated suppression of IFNγ and granzyme B expression in activated CD8+T-cells. Of note, bortezomib reversed tumor-induced downregulation of Notch receptors, Notch1 and Notch2, as well as increased the levels of cleaved Notch intracellular domain (NICD) and downstream targets Hes1 and Hey1 in tumor-draining CD8+T-cells. Moreover, bortezomib promoted CD8+T-cell nuclear factor-κB (NFκB) activity by increasing the total and phosphorylated levels of the IκB kinase and IκBα as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NFκB activity by Bay-11-7082, or NICD cleavage by γ-secretase inhibitor, bortezomib significantly increased expression of Notch Hes1 and Hey1 genes as well as perforin, granzyme B and eomesodermin in activated CD8+T-cells. Data suggest that bortezomib can rescue tumor-induced dysfunction of CD8+T-cells by its intrinsic stimulatory effects promoting NICD-NFκB crosstalk. These findings provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death but also to provide lymphocyte-stimulatory effects, thereby overcoming immunosuppressive actions of tumor on anti-tumor T-cell functions.
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA.
authors.forename: Menaka C
authors.initials: MC
authors.lastname: Thounaojam
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA.
authors.forename: Duafalia F
authors.initials: DF
authors.lastname: Dudimah
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA.|Department of Microbiology and Immunology, School of Medicine, Meharry Medical College, Nashville, TN, USA.|School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Pellom
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA.
authors.forename: Roman V
authors.initials: RV
authors.lastname: Uzhachenko
authors.affiliation: Department of Medicine, James Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.affiliation: Department of Medicine, James Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Dikov
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA.|School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA.|Host-Tumor Interactions Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Shanker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D011905:Genes, ras; D053804:Granzymes / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000378:metabolism; D000072056:Transcription Factor HES-1; D019139:Tumor Escape; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D000069286:Bortezomib; D018797:Cell Cycle Proteins; D053804:Granzymes; D018398:Homeodomain Proteins; D016328:NF-kappa B; D052899:Pore Forming Cytotoxic Proteins; D061988:Proteasome Inhibitors; D051880:Receptors, Notch; D020825:T-Box Domain Proteins; D000072056:Transcription Factor HES-1; D016159:Tumor Suppressor Protein p53; C491198:Eomes protein, mouse; C489734:Hes1 protein, mouse; C120420:Hey1 protein, mouse; C495901:TP53 protein, human; C483886:perforin, mouse; C509214:Gzmb protein, mouse
keywords: Immune response; Immunity; Immunology and Microbiology Section; NF-κB; Notch signaling; T cell Immunotherapy; cancer immunosuppression; proteasome inhibition