Zhang Lulu, Zhang Siqi, Wu Wenyu, Wang Xingkai, Shen Jieting, Wang Dongyuan, Hu Kuan, Zhang Ming-Rong, Wang Feng, Wang Rui
Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College.
J Vis Exp. 2023 Feb 3(192). doi: 10.3791/65047.
The development of immune checkpoint blockade therapy based on programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has revolutionized cancer therapies in recent years. However, only a fraction of patients responds to PD-1/PD-L1 inhibitors, owing to the heterogeneous expression of PD-L1 in tumor cells. This heterogeneity presents a challenge in the precise detection of tumor cells by the commonly used immunohistochemistry (IHC) approach. This situation calls for better methods to stratify patients who will benefit from immune checkpoint blockade therapy, to improve treatment efficacy. Positron emission tomography (PET) enables real-time visualization of the whole-body PD-L1 expression in a noninvasive way. Therefore, there is a need for the development of radiolabeled tracers to detect PD-L1 distribution in tumors through PET imaging. Compared to their L-counterparts, dextrorotary (D)-peptides have properties such as proteolytic resistance and remarkably prolonged metabolic half-lives. This study designed a new method to detect PD-L1 expression based on PET imaging of Ga-labeled PD-L1-targeted D-peptide, a D-dodecapeptide antagonist (DPA), in tumor-bearing mice. The results showed that the [Ga]DPA can specifically bind to PD-L1-overexpressing tumors in vivo, and showed favorable stability as well as excellent imaging ability, suggesting that [Ga]DPA-PET is a promising approach for the assessment of PD-L1 status in tumors.
近年来，基于程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）的免疫检查点阻断疗法彻底改变了癌症治疗方法。然而，由于肿瘤细胞中PD-L1表达的异质性，只有一小部分患者对PD-1/PD-L1抑制剂有反应。这种异质性给常用的免疫组织化学（IHC）方法精确检测肿瘤细胞带来了挑战。这种情况需要更好的方法来对将从免疫检查点阻断疗法中受益的患者进行分层，以提高治疗效果。正电子发射断层扫描（PET）能够以非侵入性方式实时可视化全身PD-L1表达。因此，需要开发放射性标记示踪剂，通过PET成像检测肿瘤中PD-L1的分布。与左旋（L）对应物相比，右旋（D）肽具有抗蛋白水解和代谢半衰期显著延长等特性。本研究设计了一种基于镓标记的靶向PD-L1的D肽（一种D-十二肽拮抗剂，DPA）在荷瘤小鼠中的PET成像来检测PD-L1表达的新方法。结果表明，[镓]DPA在体内能特异性结合过表达PD-L1的肿瘤，具有良好的稳定性和出色的成像能力，表明[镓]DPA-PET是评估肿瘤中PD-L1状态的一种有前景的方法。
