title: OK-432 synergizes with IFN-γ to confer dendritic cells with enhanced antitumor immunity.
abstract: Generation of functional dendritic cells (DCs) with boosted immunity after the withdrawal of initial activation/maturation conditions remains a significant challenge. In this study, we investigated the impact of a newly developed maturation cocktail consisting of OK-432 and interferon-gamma (IFN-γ) on the function of human monocyte-derived DCs (MoDCs). We found that OK-432 plus IFN-γ stimulation could induce significantly stronger expression of surface molecules, production of cytokines, as well as migration of DCs compared with OK-432 stimulation alone. Most importantly, DCs matured with OK-432 plus IFN-γ-induced maintained secretion of interleukin-12 (IL-12)p70 in secondary culture after stimulus withdrawal. Functionally, OK-432 plus IFN-γ-conditioned DCs induce remarkable Th1 and Tc1 responses more effectively than OK-432 alone, even more than the use of α-type-1 cytokine cocktail. As a result, DCs matured with OK-432 plus IFN-γ can prime stronger cytotoxic lymphocyte (CTL) and natural killer (NK) cell response against tumor cells in vitro. Peripheral blood mononuclear cells activated by DCs matured with OK-432 plus IFN-γ also showed greater tumor growth inhibition in vivo in null mice. Molecular mechanistic analysis showed that DC maturation using IFN-γ in concert with OK-432 involves the activation of p38 and nuclear factor-kappa B (NF-κB) pathways. This study provided a novel strategy to generate more potent immune segments in DC vaccine.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Pan
authors.affiliation: 1] State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China [2] Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Hai-xia
authors.initials: HX
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Jing-jing
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Qiu-zhong
authors.initials: QZ
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Jian-jun
authors.initials: JJ
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: De-sheng
authors.initials: DS
authors.lastname: Weng
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Dan-dan
authors.initials: DD
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Shan-shan
authors.initials: SS
authors.lastname: Jiang
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Jian-chuan
authors.initials: JC
authors.lastname: Xia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009000:Monocytes / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology*; D010844:Picibanil / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D016895:Culture Media, Serum-Free; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D010844:Picibanil; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases