title: Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells.
abstract: Murine dendritic cells (DC) transduced to express the Type-1 transactivator T-bet (i.e. mDC.Tbet) and delivered intratumorally as a therapy are superior to control wild-type DC in slowing the growth of established subcutaneous MCA205 sarcomas in vivo. Optimal antitumor efficacy of mDC.Tbet-based gene therapy was dependent on host natural killer (NK) cells and CD8(+) T cells, and required mDC.Tbet expression of major histocompatibility complex class I molecules, but was independent of the capacity of the injected mDC.Tbet to produce proinflammatory cytokines (interleukin-12 family members or interferon-γ) or to migrate to tumor-draining lymph nodes based on CCR7 ligand chemokine recruitment. Conditional (CD11c-DTR) or genetic (BATF3(-/-)) deficiency in host antigen-crosspresenting DC did not diminish the therapeutic action of intratumorally delivered wild-type mDC.Tbet. Interestingly, we observed that intratumoral delivery of mDC.Tbet (versus control mDC.Null) promoted the acute infiltration of NK cells and naive CD45RB(+) T cells into the tumor microenvironment (TME) in association with elevated expression of NK- and T-cell-recruiting chemokines by mDC.Tbet. When taken together, our data support a paradigm for extranodal (cross)priming of therapeutic Type-1 immunity in the TME after intratumoral delivery of mDC.Tbet-based gene therapy.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: J L
authors.initials: JL
authors.lastname: Taylor
authors.forename: N C
authors.initials: NC
authors.lastname: Sabins
authors.forename: D B
authors.initials: DB
authors.lastname: Lowe
authors.forename: Y
authors.initials: Y
authors.lastname: Qu
authors.forename: Z
authors.initials: Z
authors.lastname: You
authors.forename: W J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012509:Sarcoma / Q000235:genetics / Q000276:immunology / Q000628:therapy; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000276:immunology*; D014161:Transduction, Genetic; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor