title: PGE2-induced IDO1 inhibits the capacity of fully mature DCs to elicit an in vitro antileukemic immune response.
abstract: In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination. Although DC-based vaccines have raised great expectations, their clinical translation has been largely disappointing. For these results, several explanations have been proposed. In particular, the concomitant expression by DCs of tolerogenic pathways, such as the immunosuppressive agent indoleamine 2,3-dioxygenase-1 (IDO1), has been demonstrated. The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular, the role of IDO1 expression in PGE2-matured Mo-DCs has been addressed. Here we show that PGE2, which is required for full maturation of DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2-mediated expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN-γ secreting CD4(+) and CD8(+) T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2.
authors: Department of Specialistic, Diagnostic and Experimental Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, 40138 Bologna, Italy ; Ludwig Center for Cancer Research of the University of Lausanne, 1011 Lausanne, Switzerland.
authors: Sara
authors: S
authors: Trabanelli
authors: Department of Specialistic, Diagnostic and Experimental Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, 40138 Bologna, Italy.
authors: Mariangela
authors: M
authors: Lecciso
authors: Department of Specialistic, Diagnostic and Experimental Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, 40138 Bologna, Italy.
authors: Valentina
authors: V
authors: Salvestrini
authors: Department of Specialistic, Diagnostic and Experimental Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, 40138 Bologna, Italy.
authors: Michele
authors: M
authors: Cavo
authors: Department of Specialistic, Diagnostic and Experimental Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, 40138 Bologna, Italy.
authors: Darina
authors: D
authors: Očadlíková
authors: Department of Internal Medicine (DiMI), University of Genoa and IRCCS Azienda Ospedaliera Universitaria S. Martino-IST, 16132 Genoa, Italy.
authors: Roberto M
authors: RM
authors: Lemoli
authors: Department of Specialistic, Diagnostic and Experimental Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, 40138 Bologna, Italy.
authors: Antonio
authors: A
authors: Curti
mesh_terms: D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D015232:Dinoprostone