Immune-regulating MHC class I-like proteins and colorectal cancer risk

项目总结 免疫生物标记物可能有助于结直肠癌的早期发现和预防。然而，几乎没有 已知涉及主要组织相容性复合体(MHC)类I类的有效免疫途径 结直肠癌中的蛋白质。这些由胃肠道细胞表达的蛋白质是主要的配体。 自然杀伤细胞。然而，它们可能被从细胞表面切割并以可溶的形式释放到血液中。 形式-肿瘤广泛使用的逃避免疫监视的机制，即使在肿瘤的早期阶段 结直肠癌的发展。此外，MHC I类基因具有高度的多态和功能性 突变改变了这些蛋白分泌到血流中，并改变了肿瘤之间的结合 和免疫细胞。这些生物学途径为血源性结直肠癌提供了机会。 MHC-I类蛋白中和免疫治疗方法的筛选与发展 血液，尽管这些蛋白质作为结直肠癌临床生物标记物的效用仍有待确定。 我们的主要假设是MHC类I类蛋白与结直肠癌的发生风险有关。 为了验证这一新的假设，我们建议对预期人群进行二次数据分析- 基于研究--利用6种血浆MHC的现有信息在社区队列中研究动脉粥样硬化风险 在20年的随访中，对类MHC的基因分型数据进行了三次I类蛋白测量 关于结直肠癌及其危险因素的基因和数据。现有数据的使用将实现快速和成本效益 检验我们的假设。了解MHC I类蛋白在结直肠癌中的作用是临床上的 重要的是因为抑制血液中的这些蛋白质将提供一个新的机会来控制 结直肠肿瘤的发生和早期发现。 1

PROJECT SUMMARY Immune biomarkers may be useful for early detection and prevention of colorectal cancer. However, very little is known about the potent immune pathway involving major histocompatibility complex (MHC) class I-like proteins in colorectal cancer. These proteins, expressed by gastrointestinal cells, serve as major ligands for natural killer cells. However, they may be cleaved from the cell surface and released into blood in a soluble form – the mechanism widely used by tumors to escape from immune surveillance even at early stages of colorectal cancer development. In addition, MHC class I-like genes are highly polymorphic with functional mutations changing the secretion of these proteins into bloodstream and altering the binding between tumor and immune cells. These biological pathways provide opportunities for blood-based colorectal cancer screening and development of immune therapies aimed at the neutralization of MHC class I-like proteins in blood, although the utility of these proteins as clinical biomarkers in colorectal cancer remain to be determined. Our main hypothesis is that MHC class I-like proteins contribute to the risk of colorectal cancer development. To test this novel hypothesis, we propose to conduct a secondary data analysis in a prospective population- based study – Atherosclerosis Risk in the Community cohort using existing information on six plasma MHC class I-like proteins measured three times over 20 years of follow-up, genotyping data in MHC class I-like genes and data about CRC and its risk factors. The use of existing data will allow for quick and cost efficient testing of our hypothesis. Understanding the role of MHC class I-like proteins in colorectal cancer is clinically important because inhibition of these proteins in blood would provide a novel opportunity for controlling colorectal tumor development and early detection. 1