title: Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in a murine breast cancer model.
abstract: Cancer immunotherapeutic agents (vaccines) in the form of antigen-loaded dendritic cells (DCs) reached an important milestone with the recent approval of Provenge, the first DC vaccine for treatment of prostate cancer. Although this heralds a new era of tumor immunotherapy, it also highlights the compelling need to optimize such DC-based therapies as they are increasingly tested and used to treat human patients. In this study we sought to augment and enhance the antitumor activity of a DC-based vaccine using siRNA to silence expression of immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in DCs. We report here that DCs loaded with tumor antigens, but with siRNA-silenced IDO expression, were introduced into 4T1 breast tumor-bearing mice, the treatment: (i) lengthened the time required for tumor onset, (ii) decreased tumor size compared to tumors grown for equal lengths of time in mice treated with antigen-loaded DCs without IDO silencing and (iii) reduced CD4(+) and CD8(+) T cell apoptosis. Furthermore, immunization with IDO-silenced DCs enhanced tumor antigen-specific T cell proliferation and CTL activity, and decreased numbers of CD4(+) CD25(+) Foxp3(+) T(reg). This study provides evidence to support silencing of immunosuppressive genes (IDO) as an effective strategy to enhance the efficacy of DC-based cancer immunotherapeutic.
authors.affiliation: Department of Surgery, University of Western Ontario, London, Ontario, Canada. xzheng26@uwo.ca
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zheng
authors.forename: James
authors.initials: J
authors.lastname: Koropatnick
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Velenosi
authors.forename: Hong
authors.initials: H
authors.lastname: Ling
authors.forename: Xusheng
authors.initials: X
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Navarro
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Ichim
authors.forename: Bradley
authors.initials: B
authors.lastname: Urquhart
authors.forename: Weiping
authors.initials: W
authors.lastname: Min
mesh_terms: D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D007167:Immunotherapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D034741:RNA, Small Interfering