title: Genetic targeting of the active transcription factor XBP1s to dendritic cells potentiates vaccine-induced prophylactic and therapeutic antitumor immunity.
abstract: In vivo dendritic cells (DC) targeting is an attractive approach with potential advantages in vaccine efficacy, cost, and availability. Identification of molecular adjuvants to in vivo "modulate " DC to coordinately render improved Th1 and CD8 T cell immunity, and attenuated deleterious Treg effects, is a critical challenge. Here, we report that in vivo genetic targeting of the active transcription factor XBP1s to DC (XBP1s/DC) potentiated vaccine-induced prophylactic and therapeutic antitumor immunity in multiple tumor models. This immunization strategy is based on a genetic vaccine encoding both cytomegalovirus (CMV)-driven vaccine Aghsp70 and DC-specific CD11c-driven XBP1s. The novel targeted vaccine induced durable Th1 and CD8 T cell responses to poorly immunogenic self/tumor antigen (Ag) and attenuated tumor-associated Treg suppressive function. Bone marrow (BM)-derived DC genetically modified to simultaneously overexpress XBP1s and express Aghsp70 upregulated CD40, CD70, CD86, interleukin (IL)-15, IL-15Rα, and CCR7 expression, and increased IL-6, IL-12, and tumor necrosis factor (TNF)-α production in vitro. XBP1s/DC elevated functional DEC205(+)CD8α(+)DC in the draining lymph nodes (DLN). The data suggest a novel role for XBP1s in modulating DC to potentiate tumor vaccine efficacy via overcoming two major obstacles to tumor vaccines (i.e., T cell hyporesponsiveness against poorly immunologic self/tumor Ag and tumor-associated Treg-mediated suppression) and improving DEC205(+)CD8α(+)DC.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Shenghe
authors.initials: S
authors.lastname: Tian
authors.forename: Zuqiang
authors.initials: Z
authors.lastname: Liu
authors.forename: Cara
authors.initials: C
authors.lastname: Donahue
authors.forename: Louis D
authors.initials: LD
authors.lastname: Falo
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: You
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D007371:Interferon-gamma / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality; D000071701:Regulatory Factor X Transcription Factors; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory; D050052:TRPC Cation Channels / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology; D000071717:X-Box Binding Protein 1
chemical_list: D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D050052:TRPC Cation Channels; D014157:Transcription Factors; C491858:Trpc2 protein, mouse; D019444:Vaccines, DNA; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D007371:Interferon-gamma