SLFN11低表达介导的mTOR通路激活诱导免疫逃逸影响肝癌转移复发的机制研究

肝细胞癌是常见的恶性肿瘤之一，高频转移复发和耐药是其预后不良的主要原因。课题组前期整合循环肿瘤DNA外显子组和转录组数据筛选发现SLFN11低表达可介导mTOR通路激活促进肝癌增殖转移。ssGSEA和质谱流式初步发现SLFN11低表达的肝癌组织具有较高巨噬细胞和较低T细胞浸润。体外共培养发现肝癌细胞SLFN11表达改变可影响巨噬细胞极化，间接调控癌细胞PD-L1表达。RNA-Seq结果提示SLFN11可调控癌细胞多种细胞因子表达，但介导SLFN11调控巨噬细胞功能的细胞因子及机制尚不清楚。本项目拟从患者、动物和细胞三个层面研究SLFN11对巨噬细胞浸润、极化及癌细胞PD-L1的影响，并采用细胞因子中和抗体、染色质免疫共沉淀等明确SLFN11调控肝癌微环境和免疫逃逸的机制。利用小鼠模型评估免疫-靶向联合治疗抗肿瘤效果，探索SLFN11预测肝癌免疫治疗反应的可行性，为肝癌精准治疗提供可靠依据。

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Its poor prognosis is mainly due to the high rates of metastasis, recurrence, and drug-resistance. Through an integrated analysis of circulating tumor DNA exome data and transcriptome data, our group has previously identified that low SLFN11 expression can promote HCC proliferation and metastasis via the activation of mTOR pathway. By using ssGSEA and mass cytometry, we initially found that low SLFN11 expression in liver cancer tissues was associated with high macrophages infiltration and low T cells infiltration. In-vitro co-culture experiments showed that the changes of SLFN11 expression can influence the polarization of macrophages and indirectly regulate the expression of PD-L1 in HCC cells. Furthermore, RNA-Seq results showed that SLFN11 can regulate the expression of several cytokines; however, the cytokine-mediated molecular mechanism of how SLFN11 regulates the biological functions of macrophages is still unclear. Therefore, this research aims to investigate the role SLFN11 plays in macrophages’ infiltration, polarization, and PD-L1 expression in cancer cells from three different aspects (cell lines, animal models, and human patients). The mechanisms of SLFN11 regulating the HCC microenvironment and immune evasion are determined using the methods like cytokine neutralizing antibody and chromatin immunoprecipitation. By utilizing mouse models, this research also evaluates the anti-tumor efficacy of immuno-targeted combination therapy and the feasibility of SLFN11 in predicting immunotherapy response of HCC, which provides reliable basis for precision medicine of liver cancer.