夏宏光团队之前研究发现,ARIH1是PD-L1蛋白的E3连接酶,ARIH1可以促进PD-L1降解,诱导肿瘤免疫。这项新研究进一步提示,ARIH1具有降解PD-L1蛋白和改变肿瘤免疫微环境的双重功能,是具有潜力的肿瘤免疫治疗药物新靶点。 4T1是小鼠的三阴性乳腺癌...
夏宏光团队之前研究发现,ARIH1是PD-L1蛋白的E3连接酶,ARIH1可以促进PD-L1降解,诱导肿瘤免疫。这项新研究进一步提示,ARIH1具有降解PD-L1蛋白和改变肿瘤免疫微环境的双重功能,是具有潜力的肿瘤免疫治疗药物新靶点。 4T1是小鼠的三阴性乳腺癌(TNBC)细胞,是一种被广泛应用的ICB耐药肿瘤模型。研究人员发现,顺铂药物可以增...
然而作者发现,突变PD-L1(T180A和S184A)上GSK3β催化位点并不能完全阻断ES-072所诱导的PD-L1降解(图3a),表明 ES-072促进PD-L1降解的机制可能不完全依赖于GSK3β驱动。 为了确定ES-072处理后催化PD-L1 Ser279/283位点发生磷酸化的激酶,作者通...
该团队之前研究发现,ARIH1是PD-L1蛋白的E3连接酶,ARIH1可以促进PD-L降解,诱导肿瘤免疫(Wu YQ et al., Nature Communications, 2021.)。其新的工作进一步提示,ARIH1具有降解PD-L1蛋白和改变肿瘤免疫微环境的双重功能,是具有潜力的肿瘤免疫治疗药物新靶点。 4T1是小鼠的三阴性乳腺癌(TNBC)细胞,是一种被广泛应用...
针对PD-1/PD-L1抗体药物的多种不足,科学家们试图寻找可以替代抗体的小分子药物,提高疗效,降低成本,并克服抗体药物的耐药性。 2021年4月20日,Nature communications在线发表了浙江大学医学院/良渚实验室夏宏光研究员团队的最新研究成果:ARIH1 Signaling Promotes Anti-tumor Immunity by Targeting PD-L1 for Proteasomal...
该研究筛选到了一系列能降低PD-L1膜蛋白水平的先导化合物,鉴定了PD-L1蛋白新的E3泛素连接酶ARIH1,揭示了EGFR-GSK3α-ARIH1通路调控肿瘤免疫的新机制,提示ARIH1有望成为肿瘤免疫治疗的新靶点。 夏宏光团队长期致力于靶向蛋白降解的机制研究和药物开发。在该项目中,他们首先建立了基于PD-L1膜蛋白水平分析的高通量...
Cancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a
PD-L1 expression has been reported as a potential predictor of response to immunotherapy4,5,6. Although some triple-negative breast cancer (TNBC) patients have high PD-L1 expression, they are accompanied by high immunosuppression in clinical trials with PD-1 or PD-L1 blockade, as reflected by...
Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and...
PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal ...