Kline Justin, Gajewski Thomas F
University of Chicago, Department of Medicine and Pathology, Section of Hematology/Oncology, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Curr Opin Investig Drugs. 2010 Dec;11(12):1354-9.
Tumor antigen-specific T-cell function is regulated by both positive and negative costimulatory signals, which are received in the secondary lymphoid organs and within the tumor microenvironment. Tumor-induced T-cell dysfunction results from a lack of positive costimulatory signals, combined with a predominance of negative immunoregulatory mechanisms. The engagement of the protein programmed death 1 (PD1), expressed on activated T-cells, by programmed death ligand 1 (PD-L1)/B7H1 within tumor cells or other host-derived cells results in the downregulation of T-cell function, and represents an important negative regulatory pathway. Preclinical cancer models suggest that interruption of PD1/PD-L1 interactions leads to improved antitumor T-cell responses and tumor control. mAbs developed against both PD1 and PD-L1/B7H1 are being evaluated in phase I/II clinical trials in patients with a variety of cancers. The uncoupling of negative immune regulatory pathways therefore represents an exciting and potentially highly valuable new modality for cancer immunotherapy.
肿瘤抗原特异性T细胞功能受正性和负性共刺激信号调节，这些信号在二级淋巴器官和肿瘤微环境中接收。肿瘤诱导的T细胞功能障碍是由于缺乏正性共刺激信号，以及负性免疫调节机制占优势。肿瘤细胞或其他宿主来源细胞内的程序性死亡配体1（PD-L1）/B7H1与活化T细胞上表达的程序性死亡蛋白1（PD1）结合，导致T细胞功能下调，这是一条重要的负性调节途径。临床前癌症模型表明，中断PD1/PD-L1相互作用可改善抗肿瘤T细胞反应并控制肿瘤。针对PD1和PD-L1/B7H1开发的单克隆抗体正在多种癌症患者的I/II期临床试验中进行评估。因此，负性免疫调节途径的解偶联代表了一种令人兴奋且可能具有极高价值的癌症免疫治疗新方法。
