Characterization of the Role of Interferon-producing Killer Dendritic Cells in Antitumor Immunity: Potential Implications for Immunotherapy in Medullary Thyroid Carcinoma

树突状细胞是一种高效的抗原呈递细胞。最近，在小鼠中发现了一种全新的DC亚型。这些细胞不同于传统的树突状细胞和浆细胞样树突状细胞，具有自然杀伤（NK）细胞和树突状细胞的分子表达谱。由于它们能够产生大量的I型干扰素，并能够通过肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）途径杀死靶细胞，因此被称为干扰素产生杀手型dc （ikdc）。根据我们的初步数据，通过IFN¿途径由单核细胞产生的dc表达NK细胞标记物（包括TRAIL），因此可能类似于ikdc样人类细胞。基于这些数据和申请人在DC免疫治疗内分泌恶性肿瘤方面的经验，将遵循两个主要目标：首先，分析来自正常志愿者的IFN产生的人DC，以鉴定人IKDC并将这些细胞用于体外实验治疗甲状腺髓样癌（MTC）；其次，分析小鼠IKDC在接种IKDC后，在携带MTC的免疫缺陷小鼠和转基因MTC小鼠中的作用。小鼠ikdc将通过使用不同的toll样受体配体激活，并通过其迁移能力进行分析。这些研究的结果为今后MTC的疫苗接种试验奠定了基础。

Dendritic cells (DCs) are highly potent antigen-presenting cells. Very recently, a completely new DC subtype has been described in mice. These cells are distinct from conventional DCs and plasmocytoid DCs with the molecular expression profile of both natural killer (NK) cells and DCs. They are termed as interferon-producing killer DCs (IKDCs) due to their ability to produce substantial amounts of type I interferons and the ability of killing target cells via tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) pathways. According to our preliminary data, DCs generated from monocytes over the IFN¿ pathway express NK cell marker (including TRAIL) and may therefore resemble IKDC-like human cells. Based on these data and the applicant¿s experience in DC immunotherapy in endocrine malignancies, two major objectives will be followed: first, to analyze IFN¿-generated human DCs from normal volunteers in order to identify human IKDCs and to use these cells in in vitro experiments for the treatment of medullary thyroid carcinoma (MTC) and second, to analyze the role of murine IKDCs in MTC bearing immunodeficient mice and transgenic MTC mice following IKDC vaccination. Murine IKDCs will be activated by using different Toll-like receptor ligands and will also be analyzed by their migratory capacity. The results of these studies represent the basis for a future vaccination trial in MTC.