Department of Radiology and Nuclear Medicine, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
Cancer Immunol Res. 2019 Jan;7(1):150-161. doi: 10.1158/2326-6066.CIR-18-0280. Epub 2018 Nov 20.
Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive responses in subgroups of patients with cancer. PD-L1 expression in tumors seems to be a prerequisite for treatment response. However, PD-L1 is heterogeneously expressed within tumor lesions and may change upon disease progression and treatment. Imaging of PD-L1 could aid in patient selection. Previously, we showed the feasibility to image PD-L1 tumors in immunodeficient mice. However, PD-L1 is also expressed on immune cell subsets. Therefore, the aim of this study was to assess the potential of PD-L1 micro single-photon emission tomography/computed tomography (microSPECT/CT) using radiolabeled PD-L1 antibodies to (i) measure PD-L1 expression in two immunocompetent tumor models (syngeneic mice and humanized mice harboring PD-L1 expressing immune cells) and (ii) monitor therapy-induced changes in tumor PD-L1 expression. We showed that radiolabeled PD-L1 antibodies accumulated preferentially in PD-L1 tumors, despite considerable uptake in certain normal lymphoid tissues (spleen and lymph nodes) and nonlymphoid tissues (duodenum and brown fat). PD-L1 microSPECT/CT imaging could also distinguish between high and low PD-L1-expressing tumors. The presence of PD-L1 immune cells did not compromise tumor uptake of the human PD-L1 antibodies in humanized mice, and we demonstrated that radiotherapy-induced upregulation of PD-L1 expression in murine tumors could be monitored with microSPECT/CT imaging. Together, these data demonstrate that PD-L1 microSPECT/CT is a sensitive technique to detect variations in tumor PD-L1 expression, and in the future, this technique may enable patient selection for PD-1/PD-L1-targeted therapy.
阻断程序性死亡配体 1（PD-L1）与 PD-1 相互作用的抗体在癌症患者亚组中显示出令人印象深刻的反应。肿瘤中 PD-L1 的表达似乎是治疗反应的先决条件。然而，PD-L1 在肿瘤病变内呈异质性表达，并可能随着疾病进展和治疗而改变。PD-L1 的成像可能有助于患者选择。以前，我们已经证明了在免疫缺陷小鼠中对 PD-L1 肿瘤进行成像的可行性。然而，PD-L1 也在免疫细胞亚群上表达。因此，本研究的目的是评估使用放射性标记的 PD-L1 抗体进行 PD-L1 微单光子发射断层扫描/计算机断层扫描（microSPECT/CT）的潜力，以（i）测量两种免疫活性肿瘤模型（同种小鼠和携带表达 PD-L1 的免疫细胞的人源化小鼠）中的 PD-L1 表达，（ii）监测肿瘤 PD-L1 表达的治疗诱导变化。我们表明，放射性标记的 PD-L1 抗体优先在 PD-L1 肿瘤中积累，尽管在某些正常淋巴组织（脾脏和淋巴结）和非淋巴组织（十二指肠和棕色脂肪）中也有相当大的摄取。PD-L1 microSPECT/CT 成像还可以区分高表达和低表达 PD-L1 的肿瘤。在人源化小鼠中，PD-L1 免疫细胞的存在并没有影响人 PD-L1 抗体对肿瘤的摄取，并且我们证明了用 microSPECT/CT 成像可以监测放射治疗诱导的小鼠肿瘤中 PD-L1 表达的上调。总之，这些数据表明 PD-L1 microSPECT/CT 是一种灵敏的技术，可以检测肿瘤 PD-L1 表达的变化，并且在未来，该技术可能能够为 PD-1/PD-L1 靶向治疗选择患者。
