hCG-β调节肿瘤Treg及其干预治疗的机理研究

Human chorionic gonadotropin (hCG) is not only a reproductive hormone critical for maintenance of pregnancy, but the β subunit (hCG-β) of which also a tumor-associated antigen that ectopically expressed on a variety of human cancers including pancreatic cancer. It has been established that hCG-β is closely related with tumorigenesis, progression, and a strong indicator of poor prognosis in malignance. However, the mechanism is not very clear. Recently, it is reported hCG attracts regulatory T cell (Treg) to the uterus and hence contributes to maternal tolerance toward the fetus. But the relationship between hCG-β and Treg in cancer has not been reported until now. In our previous study, we have designed and constructed an anti-hCG-β tumor cell vaccine modified with hCGβ-Arg9 fusion gene, showing a significant antitumor efficacy, and found less Treg in lymph nodes of mice treated with the vaccine compared with controls. Therefore, we propose that Treg could be recruited by hCG-β in tumor microenvironment, contributing to tumor immune tolerance. Here, we’ll investigate the relationship between hCG-β and Treg in cancers, research the efficacy and mechanism of the anti-hCG-β tumor cell vaccine.

人绒毛膜促性腺激素（hCG）不仅是一种对维持妊娠至关重要的生殖激素，同时其β亚基（hCG-β）也是一种在胰腺癌等多种肿瘤广泛表达的肿瘤相关抗原，与肿瘤的发生、发展及不良预后密切相关，然而hCG-β发挥作用的机制尚未明确。近来研究发现胎盘可通过hCG募集调节性T细胞（Treg）诱导母体对胚胎的免疫耐受，但在肿瘤中hCG与免疫微环境的关系鲜有报道。前期研究中我们通过将hCG-β与一种细胞穿透肽Arg9的融合基因导入肿瘤细胞并辐照灭活，构建了一种抗hCG-β的肿瘤细胞疫苗，发现其可发挥保护性抗肿瘤作用，且疫苗干预后的小鼠淋巴结Treg数量较对照显著下降。我们推测hCG-β募集Treg诱导肿瘤细胞免疫耐受是高表达hCG-β肿瘤预后不良的重要机制。本课题拟在前期工作的基础上研究肿瘤中hCG-β调节Treg的作用及其机制，验证抗hCG-β肿瘤细胞疫苗的有效性，探讨这种干预治疗发挥作用的深入机制。

背景：人绒毛膜促性腺激素(hCG)既是一种维持妊娠的生殖激素，同时其β亚基(hCG -β)也是一种在胰腺癌等多种肿瘤广泛表达的肿瘤相关抗原，与肿瘤的发生、发展及不良预后密切相关，然而hCG-β发挥作用的机制尚未明确。近来研究发现胎盘可通过hCG募集调节性T 细胞(Treg)诱导母体对胚胎的免疫耐受，但在肿瘤中hCG与免疫微环境的关系鲜有报道。主要研究内容：通过临床标本和动物实验研究肿瘤中hCG-β调节Treg的作用，探讨抗hCG-β肿瘤细胞疫苗这种干预治疗发挥作用的深入机制。重要结果：临床胰腺癌标本行流式细胞术检测Treg细胞和外周血hCG-β检测发现Treg比例与外周血hCG-β，相关性研究分析显示两者之间R值为0.7598，有一定的相关性；回顾性分析胰腺癌临床病理标本，免疫组化检测hCG-β和Foxp3，并进行评分，发现hCG-β高表达组Foxp3平均评分较高；小鼠实验发现高表达hCG-β的肿瘤瘤内Treg比例较对照明显增高，而脾脏Treg细胞比例较对照下降，提示hCG-β可能发挥募集Treg细胞至肿瘤周围；抗hCG-β肿瘤细胞疫苗具有保护性抗肿瘤作用但却未发现显著的治疗性抗肿瘤作用。科学意义：本研究从胎盘分泌大量hCGβ从而募集Treg细胞抵抗自身免疫对胎儿的攻击的现象入手，发现肿瘤也可能利用该机制募集Treg细胞抵抗免疫系统对自己的攻击，提出了广谱肿瘤相关抗原hCGβ促进肿瘤生长演进的一种新的机制，为抗肿瘤免疫治疗提供一种新的思路。