PDF(Pubmed)
Abstract：
While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
摘要：
虽然传统观点最初假定PD-L1充当PD-1的惰性配体，但新兴的文献表明PD-L1在免疫和癌细胞中具有细胞固有功能。根据这些研究,在这里，我们显示PD-L1通过细胞配体或激动性抗体的参与，包括那些在诊所使用的，有效抑制癌细胞中的I型干扰素途径。抑制表达PD-L1的癌细胞中的I型干扰素反应导致溶瘤病毒在体外和体内的功效增强。始终如一，PD-L1表达标记了来自被溶瘤病毒感染的癌症患者的肿瘤外植体。机械上,PD-L1促进代谢转变，其特征在于糖酵解速率增加，导致乳酸产生增加。反过来,乳酸抑制I型IFN应答。除了增加对PD-L1内在功能的机械洞察外，我们的研究结果也将有助于指导临床试验中许多正在进行的将PD-L1抗体与溶瘤病毒治疗相结合的努力.
