Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Aging (Albany NY). 2023 Mar 22;15(6):1791-1807. doi: 10.18632/aging.204598.
Antibodies targeting the PD-1 receptor and its ligand PD-L1 have shown impressive responses in some tumors of bad prognosis. We hypothesized that, since immunosuppressive cells might present several immune checkpoints on their surface, the selective elimination of PD-L1 expressing cells could be efficacious in enabling the activation of antitumoral immune responses. To address this question, we developed an inducible suicidal knock-in mouse allele of (PD-L1) which allows for the tracking and specific elimination of PD-L1-expressing cells in adult tissues. Consistent with our hypothesis, elimination of PD-L1 expressing cells from the mouse peritoneum increased the septic response to lipopolysaccharide (LPS), due to an exacerbated inflammatory response to the endotoxin. In addition, mice depleted of PD-L1 cells were resistant to colon cancer peritoneal allografts, which was associated with a loss of immunosuppressive B cells and macrophages, concomitant with an increase in activated cytotoxic CD8 T cells. Collectively, these results illustrate the usefulness of PD-L1 mice for research in immunotherapy and provide genetic support to the concept of targeting PD-L1 expressing cells in cancer.
靶向 PD-1 受体及其配体 PD-L1 的抗体在一些预后不良的肿瘤中显示出令人印象深刻的反应。我们假设，由于免疫抑制细胞表面可能存在几种免疫检查点，因此选择性消除表达 PD-L1 的细胞可能有助于激活抗肿瘤免疫反应。为了解决这个问题，我们开发了一种可诱导的自杀性敲入小鼠 PD-L1（）等位基因，可用于在成年组织中跟踪和特异性消除表达 PD-L1 的细胞。与我们的假设一致，从小鼠腹膜中消除表达 PD-L1 的细胞会增加对脂多糖（LPS）的败血症反应，这是由于对内毒素的炎症反应加剧。此外，耗尽 PD-L1 细胞的小鼠对结肠癌腹膜同种异体移植物具有抗性，这与免疫抑制 B 细胞和巨噬细胞的丧失以及激活的细胞毒性 CD8 T 细胞的增加有关。总的来说，这些结果说明了 PD-L1 小鼠在免疫治疗研究中的有用性，并为靶向癌症中表达 PD-L1 的细胞的概念提供了遗传支持。
