The function and regulation of histocompatibility antigen 60 in cancer

描述（由申请人提供）：该基金的重点是研究H60的功能和调节。H60是一种NKG 2D配体，因此参与免疫受体NKG 2D对病毒感染细胞和癌细胞的识别。NKG 2D配体在感染细胞的表面上表达，以警告免疫系统病毒感染，但有趣的是，它也存在于癌细胞而不是正常细胞中。然而，将NKG 2D配体H60置于癌细胞表面的信号是未知的。已有研究表明干扰素下调H60而非其他NKG 2D配体。本研究围绕以下问题展开：NF-kB和STAT 1通路是否在调节H60表达中提供相反的活性？H60基因座如何参与肿瘤细胞H60表达的调控？肿瘤细胞上H60的表达是否降低了干扰素免疫治疗的疗效？ 为了解决这些问题，H60的调节将在一组具有天然高和低水平H60的肿瘤细胞系中使用激活和抑制NF-kB或STAT 1通路的遗传和药理学试剂进行研究。与这些实验平行，将检查H60的基因座中介导H60顺式活化的调节位点。这些实验是由初步研究，从细菌人工染色体映射的基因组位点的H60促进。 为了检查干扰素对H60的下调是否限制了其抗肿瘤作用，将具有高和低水平H60的细胞系移植到用干扰素-α处理的小鼠中。预期干扰素治疗仅在表达H60的细胞系中抑制自然杀伤细胞的肿瘤监视。这些实验的目的是生成临床前数据，以支持使用H60或相关NKG 2D配体作为生物标志物来预测干扰素免疫疗法的疗效。 总之，许多癌细胞被免疫系统识别，因为它们在细胞表面展示NKG 2D配体，这将癌细胞鉴定为异常细胞。该基金旨在了解NKG 2D配体H60的功能和调节。了解H60如何放置在肿瘤细胞表面可以帮助增强免疫介导的癌症检测和破坏。

DESCRIPTION (provided by applicant): The focus of this grant is to study the function and regulation of H60. H60 is an NKG2D ligand, and as such, participates in the recognition of virally infected cells and cancer cells by the immunoreceptor NKG2D. NKG2D ligands are expressed on the surface of infected cells to alert the immune system to viral infection, but interestingly are also found on cancer cells but not normal cells. However, the signals that place the NKG2D ligand H60 on the surface of cancer cells are unknown. It has been shown that the interferons down-regulate H60 but not other NKG2D ligands, This proposal centers on the following questions: Do the NF-kB and STAT1 pathways provide opposing activity in the regulation H60 expression? How is the H60 locus involved in the regulation of H60 expression on tumor cells? Does the expression of H60 on tumor cells diminish the efficacy of interferon immunotherapy? To address these questions, the regulation of H60 will be studied in a panel of tumor cell lines with naturally high and low levels of H60 using genetic and pharmacologic reagents that activate and inhibit the NF-kB or STAT1 pathways. In parallel to these experiments, the locus of H60 will be examined for regulatory sites that mediate the cis activation of H60. These experiments are facilitated by preliminary studies which map the genomic locus of H60 from a bacterial artificial chromosome. To examine whether the down-regulation of H60 by interferon limits its anti-tumor effect, cell lines with high and low levels of H60 will be transplanted into mice treated with interferon-alpha. The interferon treatment is expected to inhibit tumor surveillance by natural killer cells only in cell lines that express H60. The goal of these experiments is to generate pre-clinical data to support the use of H60 or related NKG2D ligands as biomarkers to predict the efficacy of interferon immunotherapy. In sum, many cancer cells are recognized by the immune system because they display NKG2D ligands at the cell surface which identify the cancer cell as an abnormal cell. This grant proposes to understand the function and regulation of the NKG2D ligand H60. An understanding of how H60 is placed on the tumor cell surface can help to enhance the immune-mediated detection and destruction of cancer.