title: Silencing of indoleamine 2,3-dioxygenase enhances dendritic cell immunogenicity and antitumour immunity in cancer patients.
abstract: Dendritic cells (DCs) are being explored as a therapeutic vaccine for cancers. However, their immunogenic potential is limited by the presence of immunosuppressive factors. Among these factors is the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). In this study, we have investigated the safety, immunogenicity and clinical response of IDO-silenced DC vaccine in four patients with gynecological cancers. DCs were transfected with IDO small interfering RNA and mRNA encoding human telomerase reverse transcriptase (hTERT) or survivin, two universal tumour antigens. Silencing of IDO in DCs did not affect the expression of the co-stimulatory molecules CD80 and CD86, but enhanced the expression of the CCR7 and CD40 molecules. IDO-silenced DCs showed superior potency to activate allogeneic T cells compared to their IDO-positive counterparts. The immunisation with this novel DC cancer vaccine was well tolerated and all patients developed delayed-type hypersensitivity skin reaction and specific T-cell response against hTERT and survivin tumour antigens. Perhaps most importantly, the immune response seen in the patients was related to objective clinical response. Thus, IDO silencing can enhance the immunogenic function of DCs in vitro and in vivo. Overall, the data provide proof-of-principle that immunisation with IDO-silenced DC vaccine is safe and effective in inducing antitumour immunity.
authors.affiliation: Department of Immunology, Oslo University Radium Hospital, Montebello, N-0310 Oslo, Norway. mosioud@medisin.uio.no
authors.forename: Mouldy
authors.initials: M
authors.lastname: Sioud
authors.forename: Stein
authors.initials: S
authors.lastname: Saebøe-Larssen
authors.forename: Thea Eline
authors.initials: TE
authors.lastname: Hetland
authors.forename: Janne
authors.initials: J
authors.lastname: Kaern
authors.forename: Anne
authors.initials: A
authors.lastname: Mobergslien
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kvalheim
mesh_terms: D019496:Cancer Vaccines / Q000008:administration & dosage; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D005833:Genital Neoplasms, Female / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D000077022:Survivin; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D019496:Cancer Vaccines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; C509186:TERT protein, human; D019098:Telomerase