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(DC)是一种高效的抗原提呈细胞。最近，在小鼠身上描述了一种全新的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相关的凋亡诱导配体(TRAIL)途径杀伤靶细胞，因此被称为干扰素产生杀伤DC(IKDC)。根据我们的初步数据，通过干扰素途径从单核细胞产生的DC表达NK细胞标志(包括TRAIL)，因此可能类似于IKDC样人细胞。基于这些数据和申请者S在DC免疫治疗内分泌恶性肿瘤方面的经验，本研究将实现两个主要目标：一是分析正常志愿者来源的干扰素β产生的DC，以鉴定人的IKDC，并将其用于体外实验中治疗甲状腺髓样癌；二是分析小鼠IKDC在免疫缺陷小鼠和IKDC疫苗接种后转基因MTC小鼠中的作用。小鼠IKDC将被不同的Toll样受体配体激活，并将根据它们的迁移能力进行分析。这些研究的结果为今后在MTC进行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.