title: Glycogen Synthase Kinase-3β (GSK-3β) Inhibition Enhances Dendritic Cell-based Cancer Vaccine Potency via Suppression of Interferon-γ-induced Indoleamine 2,3-Dioxygenase Expression.
abstract: Indoleamine 2,3-dioxygenase (IDO) functions as a crucial mediator of tumor-mediated immune tolerance by causing T-cell suppression via tryptophan starvation in a tumor environment. Glycogen synthase kinase-3β (GSK-3β) is also involved in immune and anti-tumor responses. However, the relativity of these proteins has not been as well defined. Here, we found that GSK-3β-dependent IDO expression in the dendritic cell (DC) plays a role in anti-tumor activity via the regulation of CD8(+) T-cell polarization and cytotoxic T lymphocyte activity. By the inhibition of GSK-3β, attenuated IDO expression and impaired JAK1/2-Stat signaling crucial for IDO expression were observed. Protein kinase Cδ (PKCδ) activity and the interaction between JAK1/2 and Stat3, which are important for IDO expression, were also reduced by GSK-3β inhibition. CD8(+) T-cell proliferation mediated by OVA-pulsed DC was blocked by interferon (IFN)-γ-induced IDO expression via GSK-3β activity. Specific cytotoxic T lymphocyte activity mediated by OVA-pulsed DC against OVA-expressing EG7 thymoma cells but not OVA-nonexpressing EL4 thymoma cells was also attenuated by the expressed IDO via IFN-γ-induced activation of GSK-3β. Furthermore, tumor growth that was suppressed with OVA-pulsed DC vaccination was restored by IDO-expressing DC via IFN-γ-induced activation of GSK-3β in an OVA-expressing murine EG7 thymoma model. Taken together, DC-based immune response mediated by interferon-γ-induced IDO expression via GSK-3β activity not only regulates CD8(+) T-cell proliferation and cytotoxic T lymphocyte activity but also modulates OVA-pulsed DC vaccination against EG7 thymoma.
authors: From the Department of Infectious Diseases, Armed Forces Medical Research Institute, 90bun, Jaunro, Yuseong-gu, Daejeon 305-878 and nkt2062@hanmail.net.
authors: Kyung Tae
authors: KT
authors: Noh
authors: the Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, Konkuk University School of Medicine, Chungju 380-701, South Korea.
authors: Kwang Hee
authors: KH
authors: Son
authors: the Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, Konkuk University School of Medicine, Chungju 380-701, South Korea.
authors: In Duk
authors: ID
authors: Jung
authors: the Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, Konkuk University School of Medicine, Chungju 380-701, South Korea.
authors: Tae Heung
authors: TH
authors: Kang
authors: From the Department of Infectious Diseases, Armed Forces Medical Research Institute, 90bun, Jaunro, Yuseong-gu, Daejeon 305-878 and.
authors: Chang Hun
authors: CH
authors: Choi
authors: the Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, Konkuk University School of Medicine, Chungju 380-701, South Korea immun3023@kku.ac.kr.
authors: Yeong-Min
authors: YM
authors: Park
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology; D000970:Antineoplastic Agents / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: cancer biology; cancer vaccine; dendritic cell; glycogen synthase kinase 3 (GSK-3); indoleamine-pyrrole 2,3-dioxygenase (IDO1); interferon