Center for Cancer Immune Therapy, Department of Hematology and Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej, Herlev, Denmark.
Cancer Res. 2013 Mar 15;73(6):1764-76. doi: 10.1158/0008-5472.CAN-12-3507. Epub 2013 Jan 17.
PD-L1 (CD274) contributes to functional exhaustion of T cells and limits immune responses in patients with cancer. In this study, we report the identification of an human leukocyte antigen (HLA)-A2-restricted epitope from PD-L1, and we describe natural, cytolytic T-cell reactivity against PD-L1 in the peripheral blood of patients with cancer and healthy individuals. Notably, PD-L1-specific T cells were able not only to recognize and kill tumor cells but also PD-L1-expressing dendritic cells in a PD-L1-dependent manner, insofar as PD-L1 ablation rescued dendritic cells from killing. Furthermore, by incubating nonprofessional antigen-presenting cells with long peptides from PD-L1, we found that PD-L1 was rapidly internalized, processed, and cross-presented by HLA-A2 on the cell surface. Apparently, this cross-presentation was TAP-independent, as it was conducted not only by B cells but in addition by TAP-deficient T2-cells. This is intriguing, as soluble PD-L1 has been detected in the sera from patients with cancer. PD-L1-specific CTL may boost immunity by the killing of immunosuppressive tumor cells as well as regulatory cells. However, PD-L1-specific CTLs may as well suppress immunity by the elimination of normal immune cells especially PD-L1 expressing mature dendritic cells.
PD-L1（CD274）有助于 T 细胞的功能耗竭，并限制癌症患者的免疫反应。在这项研究中，我们报告了从 PD-L1 中鉴定出一个人类白细胞抗原（HLA）-A2 限制性表位，并且我们描述了癌症患者和健康个体外周血中针对 PD-L1 的天然细胞毒性 T 细胞反应。值得注意的是，PD-L1 特异性 T 细胞不仅能够识别和杀死肿瘤细胞，而且还能够以 PD-L1 依赖性方式杀死表达 PD-L1 的树突状细胞，只要 PD-L1 的缺失能够挽救树突状细胞免于杀伤。此外，通过用 PD-L1 的长肽孵育非专业抗原呈递细胞，我们发现 PD-L1 可迅速被内吞、加工并在细胞表面由 HLA-A2 交叉呈递。显然，这种交叉呈递是不依赖于 TAP 的，因为它不仅由 B 细胞进行，而且还由 TAP 缺陷的 T2 细胞进行。这很有趣，因为癌症患者的血清中已经检测到可溶性 PD-L1。PD-L1 特异性 CTL 可以通过杀死免疫抑制性肿瘤细胞和调节性细胞来增强免疫力。然而，PD-L1 特异性 CTL 也可以通过消除正常免疫细胞，特别是表达 PD-L1 的成熟树突状细胞，来抑制免疫。
