Identification and characterisation of the expression, regulation and function as well as the clinical relevance of HLA-G regulatory microRNAs in solid tumors

非经典HLA-G分子在不同来源的人类肿瘤中经常过表达。通过与免疫效应细胞的不同受体相互作用，HLA-G阳性细胞逃避T细胞和NK细胞的免疫监视。这种HLA-G的异常表达是由不同的分子机制介导的，例如表观遗传、转录和转录后控制。近年来，一些HLA-G特异性microRNA被鉴定出来，它们下调HLA-G的表达，从而调节抗病毒和抗肿瘤免疫应答。该项目的目的是（i）系统地鉴定调节肿瘤中组成性和受调节的HLA-G表达的人类microRNA的整个谱，（ii）表征表达模式，（iii）调节，和（iv）这些HLA-G特异性microRNA的功能以及（v）确定它们在不同组织学肿瘤中的临床相关性及其与免疫细胞浸润的相关性。(vi)此外，将使用HLA-G调节miR/miR组在体外和体内操纵肿瘤的HLA-G表达，并测试其抗肿瘤活性。该项目将有助于增加对HLA-G调节microRNA的了解，作为治疗表达HLA-G的肿瘤的新策略。

The non-classical HLA-G molecule is frequently overexpressed in human tumors of distinct origin. By interaction with different receptors of immune effector cells HLA-G-positive cells escape immune surveillance by T and NK cells. This aberrant expression of HLA-G is mediated by distinct molecular mechanisms, such as epigenetic, transcriptional and post-transcriptional control. Recently, some HLA-G specific microRNAs have been identified, which downregulate the expression of HLA-G thereby modulating the anti-viral and anti-tumoral immune response. The aim of this project is to (i) systematically identify the whole spectrum of human microRNAs, which modulate the constitutive and regulated HLA-G expression in tumors, (ii) to characterize the expression pattern, (iii) the regulation, and (iv) the function of these HLA-G specific microRNAs as well as to (v) determine their clinical relevance in tumors of distinct histology and its correlation with the immune cell infiltration. (vi) In addition, the HLA-G expression of tumors will be manipulated in vitro and in vivo using HLA-G regulating miRs/antagomiRs and tested for their anti-tumoral activity. This project will contribute to an increased knowledge of HLA-G regulatory microRNAs as novel strategy for the treatment of HLA-G expressing tumors.