title: The differential influence of allogeneic tumor cell death via DNA damage on dendritic cell maturation and antigen presentation.
abstract: Dendritic cells (DCs) respond to danger signals from tissue injury by amplifying their immune-inducing capacity. In the cancer context, this may lead to in vivo antitumor synergism between DCs and DNA-damaging chemotherapeutic agents. Neither the interaction between DCs and dying tumor cells nor whether different ways of inducing cell injury can deliver danger signals of different strength to DCs nor the potential role of damaged DNA as a danger signal has been studied rigorously. Here we report that coculture of immature DCs with tumor cells treated with the alkylating agents melphalan and chlorambucil leads to enhanced autologous and allogeneic T-cell activation, up-regulation of surface expression of MHC and costimulatory molecules, and increased interleukin (IL)-12 secretion. Exposure of the same DCs to tumor cells killed by cytarabine or by freeze-thaw (primary necrosis) resulted in significantly less T-cell proliferation and IL-12 production, indicating that DCs are able to sense and respond differentially to the mode of cell death. Exposure of DCs to DNA purified from tumor cells treated with alkylating agents also increased their T-cell-stimulating capacity, expression of CD86, and IL-12 secretion, supporting the hypothesis that the activating effects of tumor cells are linked to the nature of the DNA damage. This is the first study that shows that DCs respond differentially to killed tumor cells, depending upon the mechanism of DNA damage and consequent cell death.
authors.affiliation: Department of Immunology, Windeyer Institute of Medical Sciences, University College London, London W1T 4JF, United Kingdom.
authors.forename: Ariel N
authors.initials: AN
authors.lastname: Rad
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pollara
authors.forename: S M Afzal
authors.initials: SM
authors.lastname: Sohaib
authors.forename: Cheryl
authors.initials: C
authors.lastname: Chiang
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Chain
authors.forename: David R
authors.initials: DR
authors.lastname: Katz
mesh_terms: D017951:Antigen Presentation; D015703:Antigens, CD / Q000032:analysis; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D051940:B7-2 Antigen; D016923:Cell Death; D018920:Coculture Techniques; D004249:DNA Damage; D003713:Dendritic Cells / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000032:analysis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D020298:U937 Cells; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D018906:Antineoplastic Agents, Alkylating; D051940:B7-2 Antigen; C497964:CD86 protein, human; D008562:Membrane Glycoproteins; D018664:Interleukin-12