TWEAK调控巨噬细胞的极性抑制卵巢癌转移的研究

Tumor associated macrophages (TAM) play important roles in promoting peritoneal metastasis of epithelial ovarian cancer (EOC). Our previous study demonstrated that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) might reverse the role of TAM in promoting metastasis of EOC, however, the mechanisms underlying these interactions between TWEAK and TAM that lead to the reversal of EOC metastasis remain elusive. Our previous study have identified that TWEAK could alter the macrophages phenotype with upregulated TNF-α/IL-6 and downregulated IL-10/CD206, pushing macrophages to the M2 type. We also found that NF-κB pathway was activated through TWEAK stimulation. In the present study, we designed to use cell lines in vitro and humanized immune system mice models in vivo to explore whether TWEAK reversed the role of TAM in promoting metastasis of EOC by altering polarizaiton via NF-κB activation. Our study would shed light on the mechanisms of TWEAK regulating the effect of TAM on EOC metastasis, and investigate the.prospect for TWEAK in immunotherapy of EOC

肿瘤相关巨噬细胞（TAM）在促进上皮性卵巢癌（EOC）盆腹腔转移中起关键作用，我们前期研究报道证明，肿瘤坏死因子样凋亡微弱诱导剂（TWEAK）可逆转TAM促EOC转移的作用，但具体机制不明。靶向肿瘤相关巨噬细胞，改变巨噬细胞的极性，诱导其产生抗肿瘤效应的研究现已成为肿瘤研究中一个新的热点，其中NF-κB通路被认为是最关键的调控通路之一。我们的预实验结果提示TWEAK作用于巨噬细胞后，其M1表型标记物表达升高，而M2表型标记物表达降低，且NF-κB通路激活。本课题拟在选用细胞株进行体外实验的的基础上，建立免疫系统人源化小鼠模型以及临床标本检测来研究TWEAK处理前后巨噬细胞极性的改变及NF-κB通路的活化情况，明确TWEAK调控TAM的极性逆转TAM促EOC转移效应是否通过NF-κB通路介导，探讨TWEAK在EOC免疫治疗中的可行性。

上皮性卵巢癌（epithelial ovarian cancer, EOC）是妇科恶性肿瘤中死亡率最高的肿瘤，恶性程度极高。肿瘤的发展离不开它的“巢穴”—肿瘤微环境，肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）是肿瘤微环境中数量最多的免疫细胞，其功能特点趋向于M2型巨噬细胞，利用巨噬细胞高可塑性的特点，使巨噬细胞由M2向M1的方向重塑，可以增强抗肿瘤作用。我们前期研究报道证明，肿瘤坏死因子样凋亡微弱诱导剂（TWEAK）可逆转TAM促EOC转移的作用，但具体机制不明。在本研究中，我们从体外细胞实验、动物实验及临床标本等多方位对TWEAK对巨噬细胞极性的调控及相关机制进行深入细致地研究，通过三年刻苦工作，我们目前已经成功地证明了以下科学事实：第一，TWEAK可调控巨噬细胞的极性，使其由M2向M1的方向重塑；第二，TWEAK调控巨噬细胞的极性逆转其促EOC转移效应是通过NF-κB通路介导的；第三，TWEAK在EOC免疫治疗中具有一定的可行性。