title: The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-β receptor on dendritic cells potentiates tumour antigen-specific CD8(+) T cell immunity.
abstract: Dendritic cells (DCs) are promising therapeutic agents in the field of cancer immunotherapy due to their intrinsic immune-priming capacity. The potency of DCs, however, is readily attenuated immediately after their administration in patients as tumours and various immune cells, including DCs, produce various immunosuppressive factors such as interleukin (IL)-10 and transforming growth factor (TGF)-β that hamper the function of DCs. In this study, we used small interfering RNA (siRNA) to silence the expression of endogenous molecules in DCs, which can sense immunosuppressive factors. Among the siRNAs targeting various immunosuppressive molecules, we observed that DCs transfected with siRNA targeting IL-10 receptor alpha (siIL-10RA) initiated the strongest antigen-specific CD8(+) T cell immune responses. The potency of siIL-10RA was enhanced further by combining it with siRNA targeting TGF-β receptor (siTGF-βR), which was the next best option during the screening of this study, or the previously selected immunoadjuvant siRNA targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or Bcl-2-like protein 11 (BIM). In the midst of sorting out the siRNA cocktails, the cocktail of siIL-10RA and siTGF-βR generated the strongest antigen-specific CD8(+) T cell immunity. Concordantly, the knock-down of both IL-10RA and TGF-βR in DCs induced the strongest anti-tumour effects in the TC-1 P0 tumour model, a cervical cancer model expressing the human papillomavirus (HPV)-16 E7 antigen, and even in the immune-resistant TC-1 (P3) tumour model that secretes more IL-10 and TGF-β than the parental tumour cells (TC-1 P0). These results provide the groundwork for future clinical development of the siRNA cocktail-mediated strategy by co-targeting immunosuppressive molecules to enhance the potency of DC-based vaccines.
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University.|Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University.|Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: S-O
authors.initials: SO
authors.lastname: Hong
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University.|Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University.|Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.|Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Noh
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University.|Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: K-H
authors.initials: KH
authors.lastname: Song
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University.|Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Physiology.
authors.forename: J-H
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Korea.
authors.forename: D-W
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Division of Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University.|Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: T W
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D052162:Human papillomavirus 16; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*; D053701:Receptors, Interleukin-10 / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy / Q000821:virology
chemical_list: D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D053701:Receptors, Interleukin-10; D016212:Transforming Growth Factor beta; C059731:oncogene protein E7, Human papillomavirus type 16; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: IL-10RA; TGF-β; dendritic cell; immunotherapy; siRNA