The function and regulation of histocompatibility antigen 60 in cancer

描述(申请人提供)：本基金的重点是研究H60的功能和调节。H60是一种NKG2D配体，因此参与了免疫受体NKG2D对病毒感染细胞和癌细胞的识别。NKG2D配体表达在感染细胞的表面，以提醒免疫系统注意病毒感染，但有趣的是，在癌细胞上也发现了NKG2D配体，但正常细胞上没有。然而，将NKG2D配体H60放置在癌细胞表面的信号尚不清楚。已经证明干扰素下调H60而不是其他NKG2D配体，这一提议围绕以下问题：在调节H60的表达中，NF-kB和STAT1通路是否提供相反的活性？H60基因是如何参与调节肿瘤细胞上H60表达的？肿瘤细胞上H60的表达是否会降低干扰素免疫治疗的疗效？ 为了解决这些问题，将在一组具有自然高和低水平H60的肿瘤细胞系中研究H60的调节，使用激活和抑制NF-kB或STAT1通路的遗传和药物试剂。在这些实验的同时，将检查H60的基因座以寻找调节H60顺式激活的调控位点。这些实验是由初步研究促进的，这些研究从细菌人工染色体绘制了H60的基因组位置。 为了检验干扰素对H60的下调是否限制了它的抗肿瘤作用，我们将把高水平和低水平的H60细胞系移植到接受干扰素-α治疗的小鼠体内。干扰素治疗预计只会在表达H60的细胞系中抑制自然杀伤细胞对肿瘤的监视。这些实验的目的是产生临床前数据，以支持使用H60或相关的NKG2D配体作为生物标记物来预测干扰素免疫治疗的疗效。 总而言之，许多癌细胞被免疫系统识别是因为它们在细胞表面显示NKG2D配体，这些配体将癌细胞识别为异常细胞。这项资助旨在了解NKG2D配体H60的功能和调节。了解H60是如何被放置在肿瘤细胞表面的有助于加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.