title: Immunosuppressive factor blockade in dendritic cells via siRNAs results in objective clinical responses.
abstract: Over the past decade, immunotherapy has emerged as a promising new form of cancer treatment with the potential to eradicate tumor metastasis. However, its curative potential is in general limited by the existence of negative feedback mechanisms that control dendritic cells (DCs) and T-cell activation. For clinically effective immunity, there is a need of inhibiting the expression of these immune suppressors. This could enhance the activation of DCs, T cells, and natural killer cells, and might be beneficial for cancer immunotherapy. Among the immune inhibitory molecules expressed by DCs is indoleamine 2,3-dioxygenase (IDO), an enzyme that conveys immunosuppressive effects by degrading tryptophan, an essential amino acid required for T-cell proliferation and survival. Depletion of tryptophan by IDO-positive DCs induces T-cell apoptosis and the conversion of naïve CD4+ T cells into regulatory T cells that further suppress antitumor immunity. Herein, we describe a protocol for in vitro synthesis of small interfering RNA against IDO and other immunosuppressive factors such as interleukin-10 and programmed cell death-1 ligands in order to reverse immune suppression mediated by DCs. Vaccination with IDO-silenced DC vaccines enhanced immune responses and antitumor immunity in cancer patients.
authors.affiliation: Department of Immunology, Institute for Cancer Research, Oslo University Radium Hospital, Norway, 0310, Montebello, Oslo, Norway, mouldy.sioud@rr-research.no.
authors.forename: Mouldy
authors.initials: M
authors.lastname: Sioud
authors.forename: Anne
authors.initials: A
authors.lastname: Mobergslien
authors.forename: Stein
authors.initials: S
authors.lastname: Sæbøe-Larssen
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000138:chemical synthesis / Q000235:genetics* / Q000276:immunology; D014162:Transfection; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; D016753:Interleukin-10