Accurate predictive biomarkers of response to immune checkpoint inhibitors (ICIs) are required for better stratifying patients with cancer to ICI treatments. Here, we present a new concept for a bioassay to predict the response to anti-PD1 therapies, which is based on measuring the binding functionality of PDL1 and PDL2 to their receptor, PD1. In detail, we developed a cell-based reporting system, called the immuno-checkpoint artificial reporter with overexpression of PD1 (IcAR-PD1) and evaluated the functionality of PDL1 and PDL2 binding in tumor cell lines, patient-derived xenografts, and fixed-tissue tumor samples obtained from patients with cancer. In a retrospective clinical study, we found that the functionality of PDL1 and PDL2 predicts response to anti-PD1 and that the functionality of PDL1 binding is a more effective predictor than PDL1 protein expression alone. Our findings suggest that assessing the functionality of ligand binding is superior to staining of protein expression for predicting response to ICIs.

中文翻译：

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PD1 配体的功能性结合可预测癌症患者对抗 PD1 治疗的反应

需要准确预测免疫检查点抑制剂 (ICI) 反应的生物标志物，以便更好地对癌症患者进行 ICI 治疗分层。在这里，我们提出了一种新的生物测定概念，用于预测抗 PD1 疗法的反应，该概念基于测量 PDL1 和 PDL2 与其受体 PD1 的结合功能。详细而言，我们开发了一种基于细胞的报告系统，称为具有 PD1 过表达的免疫检查点人工报告基因 (IcAR-PD1)，并评估了 PDL1 和 PDL2 在肿瘤细胞系、患者来源的异种移植物和固定-从癌症患者身上获得的组织肿瘤样本。在一项回顾性临床研究中，我们发现 PDL1 和 PDL2 的功能可预测对抗 PD1 的反应，并且 PDL1 结合的功能是比单独的 PDL1 蛋白表达更有效的预测因子。我们的研究结果表明，评估配体结合的功能优于蛋白质表达染色来预测对 ICI 的反应。