Sun Rongqi, Liu Kaixuan, Pan Siyuan, Ye Yuhang, Li Ning, Chen Shuangyi, Cui Xinyi, Zhang Yuxi, Chen Long, Pan Jingyue, Hu Zhiqiang, Luo Chubin, Fan Jia, Zhou Zhengjun, Zhou Shaolai, Zhou Jian
Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Hepatology. 2024 Dec 24. doi: 10.1097/HEP.0000000000001212.
HCC recurrence is a major factor limiting long-term survival and the cause of most deaths in patients with HCC. However, molecular characterization and potential therapeutic targets of recurrent HCC remain mostly unknown.
We performed whole-exome sequencing in 63 matched primary and recurrent HCC tumors and combined the data with whole-genome sequencing results in 43 paired samples from our previous study. Sanger sequencing was used to identify all low-density lipoprotein receptor-related protein 4 ( LRP4 ) coding exons in 203 additional patients with recurrent HCC. We identified LRP4 somatic mutations in 7.8% (24/309) of recurrent tumors and only 0.97% (3/309) of primary tumors ( p <0.001). Prognosis after the second liver resection was poorer in patients with an LRP4 mutation. Biofunctional investigations demonstrated that inactivating LRP4 mutations promoted tumor progression and immunosuppression. Mechanistically, mutated LRP4 reduced intratumoral conventional type 1 dendritic cell and CD8 + T cell infiltration by repressing C-C motif chemokine ligand 4 expression and secretion through activation of β-catenin signaling, resulting in resistance to anti-programmed cell death protein-1 therapy. Patients with recurrent HCC carrying an LRP4 mutation did not benefit from anti-programmed cell death protein-1 treatment after their second resection surgery. A β-catenin inhibitor-reversed LRP4-induced resistance to anti-programmed cell death protein-1 therapy in humanized tumor-bearing mice.
Our results identified novel LRP4 mutations important in recurrent HCC. Inactivating LRP4 mutations were associated with resistance to anti-programmed cell death protein-1 therapy and could be useful biomarkers for precision therapy in patients with recurrent HCC.
肝癌复发是限制患者长期生存的主要因素，也是导致大多数肝癌患者死亡的原因。然而，复发性肝癌的分子特征和潜在治疗靶点大多仍不清楚。
我们对63对匹配的原发性和复发性肝癌肿瘤进行了全外显子组测序，并将数据与我们之前研究中43对样本的全基因组测序结果相结合。采用桑格测序法对另外203例复发性肝癌患者的所有低密度脂蛋白受体相关蛋白4（LRP4）编码外显子进行鉴定。我们在7.8%（24/309）的复发性肿瘤中发现了LRP4体细胞突变，而在原发性肿瘤中仅为0.97%（3/309）（p<0.001）。LRP4突变患者二次肝切除后的预后较差。生物功能研究表明，LRP4失活突变促进肿瘤进展和免疫抑制。机制上，突变的LRP4通过激活β-连环蛋白信号通路抑制C-C基序趋化因子配体4的表达和分泌，从而减少肿瘤内常规1型树突状细胞和CD8+T细胞浸润，导致对程序性细胞死亡蛋白1治疗产生抗性。携带LRP4突变的复发性肝癌患者在二次切除术后未从程序性细胞死亡蛋白1治疗中获益。β-连环蛋白抑制剂可逆转LRP4诱导的人源化荷瘤小鼠对程序性细胞死亡蛋白1治疗的抗性。
我们的研究结果确定了复发性肝癌中重要的新型LRP4突变。LRP4失活突变与程序性细胞死亡蛋白1治疗抗性相关，可能是复发性肝癌精准治疗的有用生物标志物。
