PDF(Pubmed)
Abstract：
Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.
摘要：
针对PD-1/PD-L1通路的免疫检查点抑制已成为治疗癌症的强大临床策略，但其功效因各种抗性机制而变得复杂。抗性的原因之一是抗体结合后PD-L1自身的内化和再循环。溶酶体介导的PD-L1降解的抑制对于保持再循环回到细胞膜的PD-L1的量是关键的。在这项研究中,我们发现Hsc70通过内体-溶酶体途径促进PD-L1降解,并减少PD-L1再循环到细胞膜.这种作用依赖于抑制CMTM6-PD-L1相互作用的Hsc70-PD-L1结合。我们进一步鉴定了Hsp90α/β抑制剂，AUY-922，诱导Hsc70表达和PD-L1溶酶体降解。Hsc70过表达或AUY-922治疗可以降低PD-L1表达，抑制雌性小鼠的肿瘤生长并促进抗肿瘤免疫力；AUY-922可进一步增强抗PD-L1和抗CTLA4治疗的抗肿瘤功效。我们的研究阐明了Hsc70介导的PD-L1溶酶体降解的分子机制，并为肿瘤免疫治疗提供了靶点和治疗策略。
