title: Host-derived CD8+ dendritic cells are required for induction of optimal graft-versus-tumor responses after experimental allogeneic bone marrow transplantation.
abstract: The graft-versus-tumor (GVT) effect after allogeneic hematopoietic cell transplantation (allo-HCT) represents an effective form of immunotherapy against many malignancies. Meaningful separation of the potentially curative GVT responses from graft-versus-host disease (GVHD), the most serious toxicity following T-cell replete allo-HCT, has been an elusive goal. GVHD is initiated by alloantigens, although both alloantigens and tumor-specific antigens (TSAs) initiate GVT responses. Emerging data have illuminated a role for antigen-presenting cells (APCs) in inducing alloantigen-specific responses. By using multiple clinically relevant murine models, we show that a specific subset of host-derived APCs-CD8(+) dendritic cells (DCs)-enhances TSA responses and is required for optimal induction of GVT. Stimulation of TLR3, which among host hematopoietic APC subsets is predominantly expressed on CD8(+) DCs, enhanced GVT without exacerbating GVHD. Thus, strategies that modulate host APC subsets without direct manipulation of donor T cells could augment GVT responses and enhance the efficacy of allo-HCT.
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Gary
authors.initials: G
authors.lastname: Luker
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Luker
authors.forename: Isao
authors.initials: I
authors.lastname: Tawara
authors.forename: Rebecca
authors.initials: R
authors.lastname: Evers
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Nathan
authors.initials: N
authors.lastname: Mathewson
authors.forename: Chelsea
authors.initials: C
authors.lastname: Malter
authors.forename: Evelyn
authors.initials: E
authors.lastname: Nieves
authors.forename: Sung
authors.initials: S
authors.lastname: Choi
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000502:physiology*; D016827:CD8 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020350:Graft vs Tumor Effect / Q000276:immunology* / Q000502:physiology; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014019:Tissue Donors; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016827:CD8 Antigens