Targeted siRNA Silencing of Indoleamine 2, 3-Dioxygenase in Antigen-presenting Cells Using Mannose- conjugated Liposomes: A Novel Strategy for Treatment of Melanoma
Targeted siRNA Silencing of Indoleamine 2, 3-Dioxygenase in Antigen-presenting Cells Using Mannose- conjugated Liposomes: A Novel Strategy for Treatment of Melanoma
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使用甘露糖缀合脂质体靶向 siRNA 沉默抗原呈递细胞中的吲哚胺 2, 3-双加氧酶：治疗黑色素瘤的新策略
DOI：
10.1097/cji.0000000000000022
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发表时间：
2014-02-01
影响因子：
3.9
通讯作者：
Min, Wei-Ping
中科院分区：
文献类型：
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作者：
Chen, Di;Koropatnick, James;Min, Wei-Ping
树突状细胞(DC)表达吲哚胺2，3-双加氧酶(IDO)，可抑制T细胞活化，诱导T细胞凋亡，促进T细胞分化为调节性T细胞。所有这些都可以促进宿主免疫监视系统对肿瘤的逃逸。我们假设，IDO的DC靶向基因沉默可以增强抗肿瘤免疫，从而抑制肿瘤生长。甘露糖受体在包括DC在内的抗原提呈细胞(APC)中高度表达。在本研究中，我们开发了一种新型的APC靶向的小干扰RNA传递系统，该系统使用包裹了IDO小干扰RNA的甘露糖脂质体(Man-Lipoo)，优先下调了黑色素瘤荷瘤小鼠引流淋巴结和脾中IDO的表达。接受Man-Lipo-siido治疗的小鼠表现出移植的小鼠黑色素瘤的发病时间延迟，存活时间延长，肿瘤体积缩小，来自脾和淋巴结的T细胞对黑色素瘤抗原的反应性增强。抗肿瘤免疫增强可能与抑制CD8(+)、CD4(+)T细胞以及脾和淋巴结中Treg细胞的凋亡有关。这项研究首次证明了Man-Lipo-siido可以优先靶向APC，并在体外和体内有效地沉默IDO的表达；这些事件有望增强对黑色素瘤移植瘤的抗肿瘤免疫反应。这项研究支持了曼脂siido作为免疫靶向治疗抗癌剂的发展潜力的假说。
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.