title: Targeted siRNA silencing of indoleamine 2, 3-dioxygenase in antigen-presenting cells using mannose-conjugated liposomes: a novel strategy for treatment of melanoma.
abstract: Indoleamine 2, 3-dioxygenase (IDO) expression in dendritic cells (DCs) leads to the inhibition of T-cell activation, induction of T-cell apoptosis, and promotion of T-cell differentiation into regulatory T cells. All of these could promote tumor escapement of the host's immune surveillance system. We hypothesized that DC-targeted gene silencing of IDO would enhance antitumor immunity and thus restrain tumor growth. Mannose receptors are highly expressed in antigen-presenting cells (APCs) including DCs. In this study, we developed a novel APC-targeted small interfering RNA delivery system using mannosed liposomes (Man-lipo) with encapsulated IDO small interfering RNA (Man-lipo-siIDO), which preferentially knocked down IDO expression in draining lymph node and spleen of melanoma-bearing mice. Mice treated with Man-lipo-siIDO displayed a delayed time of onset of implanted murine melanomas, increased survival time, reduced tumor size, and increased reactivity of T cells from spleen and lymph nodes against melanoma antigens. The enhanced antitumor immunity may be linked to inhibition of apoptosis in CD8 and CD4 T cells as well as Treg cells in spleen and lymph nodes. This study is the first to demonstrate that Man-lipo-siIDO can preferentially targets APCs and efficiently silence IDO expression in vitro and in vivo; events expected to enhance antitumor immune reactions against melanoma xenografts. This study supports the hypothesis that Man-lipo-siIDO may possess the potential for development as an immune-targeting therapeutic anticancer agent.
authors: *Departments of Pathology, Surgery, Oncology, Microbiology and Immunology, Physiology and Pharmacology, Western University ‡Lawson Health Research Institute †London Regional Cancer Program, London, ON, Canada §Jiangxi Academy of Medical Sciences, Institute of Immunomodulation and Immunotherapy of Nanchang University, Nanchang, China.
authors: Di
authors: D
authors: Chen
authors: James
authors: J
authors: Koropatnick
authors: Nan
authors: N
authors: Jiang
authors: Xiufen
authors: X
authors: Zheng
authors: Xusheng
authors: X
authors: Zhang
authors: Hongmei
authors: H
authors: Wang
authors: Keng
authors: K
authors: Yuan
authors: King Sun
authors: KS
authors: Siu
authors: Aminah
authors: A
authors: Shunnar
authors: Colin
authors: C
authors: Way
authors: Wei-Ping
authors: WP
authors: Min
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D037181:Lectins, C-Type / Q000737:chemistry / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D008198:Lymph Nodes / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000737:chemistry / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000628:therapy*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000628:therapy*; D013154:Spleen / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D047368:Tumor Burden / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D037181:Lectins, C-Type; D008081:Liposomes; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface