PGLYRP2蛋白在肝癌免疫应答中的功能和分子机制研究

The pattern of cancer therapy has been subverted by immunotherapy. However, due to the immunological suppression of tumor microenvironment in hepatocellular carcinoma, the efficiency of cancer immune response is not satisfied. Pattern recognition receptors (PRRs) function as the initial factors of innate immune response, and they are closely associated with remodeling of tumor microenvironment and tumor immune response. PGLYRP2 is a type of PRR that has constitutively high-level and liver-specific expression. Our preliminary study suggests that PGLYRP2 gene expression silencing in hepatocellular carcinoma (HCC) tissues is significantly negative association with survival and prognosis of patients; PGLYRP2 interacts with exosome core components EXOSC7/9, and potentially regulates the secretion of chemokines to affect immune response against hepatoma cells and the function of tumor-infiltration lymphocytes. Herein, we present the hypothesis that exosomal PGLYRP2 regulates immune response against hepatoma cells through remolding tumor microenvironment. In this study, we will combine immune active mouse model, human immune system reconstituted mouse model, single-cell RNA-sequencing and molecular methods to elucidate the relationship among PGLYRP2 gene expression, tumor microenvironment and tumor-infiltration lymphocytes. Moreover, we will discuss the function and mechanism of PGLYRP2 in regulation of immune response against HCC, from the perspective of exosome-derived protein and immune effector. Thus, this project will provide a new direction for the improved immunotherapy of hepatoma.

免疫治疗颠覆了肿瘤治疗格局，但由于肝癌肿瘤微环境具有较强的免疫抑制性，其免疫应答效果并不理想。模式识别受体作为天然免疫应答的始动因素，其功能与肿瘤微环境的改造和肿瘤免疫应答密切相关。PGLYRP2是肝脏组织特异高表达的模式识别受体，我们前期发现肝癌组织中PGLYRP2基因表达沉默与患者生存预后呈显著负相关；该蛋白与外泌体核心成分EXOSC7/9存在相互作用，并调控化学趋化因子分泌和肿瘤浸润淋巴细胞活性。基于此，我们提出“外泌体PGLYRP2蛋白通过改造肿瘤微环境调控肝癌免疫应答”的假设，拟采用免疫活性小鼠和人免疫系统重建小鼠为研究模型，结合单细胞转录组测序和分子水平的研究，探讨肝癌组织中模式识别受体PGLYRP2的表达与肿瘤微环境、肿瘤浸润淋巴细胞之间的关系，并从外泌体来源蛋白和免疫效应因子角度，阐述PGLYRP2蛋白对肝癌免疫应答的调控功能和具体机制，为改善肝癌免疫治疗效果提供新思路。

由于肝癌的抑制性免疫肿瘤微环境，肝癌临床的免疫治疗效果并不理想。而天然免疫应答对免疫治疗的促进作用不容忽视。模式识别受体作为天然免疫应答的始动因素，其功能与肿瘤微环境的改造和肿瘤免疫应答密切相关。PGLYRP2是肝脏组织特异高表达的模式识别受体，本项目的研究发现肝癌组织中PGLYRP2基因表达沉默与DNMT3A及肝癌患者生存预后呈显著负相关；该蛋白与调控化学趋化因子CCL5分泌和肿瘤浸润淋巴细胞活性。项目采用免疫活性小鼠为研究模型，结合蛋白质谱和分子水平的研究，阐明了肝癌组织中模式识别受体PGLYRP2的表达与肿瘤微环境、肿瘤浸润淋巴细胞之间的关系，并从免疫效应因子角度，阐述了PGLYRP2蛋白对肝癌免疫应答的调控机制，为改善肝癌免疫治疗效果提供新思路。