Zhao Jun, Wen Xiaoxia, Li Tingting, Shi Sixiang, Xiong Chiyi, Wang Yaoqi Alan, Li Chun
Department of Cancer Systems Imaging and Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1881 East Road, 3SCRB4.3636, Houston, Texas 77054, United States.
ACS Omega. 2020 Apr 8;5(15):8474-8482. doi: 10.1021/acsomega.9b03731. eCollection 2020 Apr 21.
: Among the treatment options for pancreatic ductal adenocarcinoma (PDAC) are antibodies against the programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway. Positron emission tomography (PET) has been successfully used to assess PD-1/PD-L1 signaling in subcutaneous tumor models, but orthotopic tumor models are increasingly being recognized as a better option to accurately recapitulate human disease. However, when PET radiotracers have high uptake in the liver and spleen, it can obscure signals from the adjacent pancreas, making visualization of the response in orthotopic pancreatic tumors technically challenging. In this study, we first investigated the impact of radioisotope chelators on the biodistribution of Cu-labeled anti-PD-1 and anti-PD-L1 antibodies and compared the distribution profiles of anti-PD-1 and anti-PD-L1 antibodies. We then tested the hypothesis that co-injection of unlabeled antibodies reduces uptake of Cu-labeled anti-PD-L1 antibodies in the spleen and thereby permits accurate delineation of orthotopic pancreatic tumors in mice. : We established subcutaneous and orthotopic mouse models of PDAC using KRAS* murine pancreatic cancer cells with a doxycycline-inducible mutation of KRAS. We then (1) compared the biodistribution of Cu-labeled anti-PD-1 with 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (-SCN-Bn-DOTA) and 2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (-SCN-Bn-NOTA) used as the chelators in the orthotopic model; (2) compared the biodistribution of [Cu]Cu-NOTA-anti-PD-1 and [Cu]Cu-NOTA-anti-PD-L1 in the orthotopic model; and (3) imaged subcutaneous and orthotopic KRAS* tumors with [Cu]Cu-NOTA-anti-PD-L1 with and without co-injection of unlabeled anti-PD-L1 as the blocking agent. : [Cu]Cu-NOTA-anti-PD-L1 was a promising imaging probe. By co-injection of an excess of unlabeled anti-PD-L1, background signals of [Cu]Cu-NOTA-anti-PD-L1 from the spleen were significantly reduced, leading to a clear delineation of orthotopic pancreatic tumors. : Co-injection with unlabeled anti-PD-L1 is a useful method for PET imaging of PD-L1 expression in orthotopic pancreatic cancer models.
胰腺导管腺癌（PDAC）的治疗选择包括针对程序性细胞死亡受体1（PD-1）/程序性细胞死亡配体1（PD-L1）通路的抗体。正电子发射断层扫描（PET）已成功用于评估皮下肿瘤模型中的PD-1/PD-L1信号传导，但原位肿瘤模型越来越被认为是更准确模拟人类疾病的更好选择。然而，当PET放射性示踪剂在肝脏和脾脏中摄取较高时，可能会掩盖来自相邻胰腺的信号，使得原位胰腺肿瘤反应的可视化在技术上具有挑战性。在本研究中，我们首先研究了放射性同位素螯合剂对铜标记的抗PD-1和抗PD-L1抗体生物分布的影响，并比较了抗PD-1和抗PD-L1抗体得分布情况。然后我们测试了一个假设，即共同注射未标记的抗体可减少铜标记的抗PD-L1抗体在脾脏中的摄取，从而能够准确描绘小鼠原位胰腺肿瘤。
我们使用具有强力霉素诱导的KRAS突变的KRAS小鼠胰腺癌细胞建立了PDAC的皮下和原位小鼠模型。然后我们：（1）在原位模型中比较了以2-（4-异硫氰酸苄基）-1,4,7,10-四氮杂环十二烷四乙酸（-SCN-Bn-DOTA）和2-（4-异硫氰酸苄基）-1,4,7-三氮杂环壬烷-1,4,7-三乙酸（-SCN-Bn-NOTA）作为螯合剂的铜标记抗PD-1的生物分布；（2）在原位模型中比较了[Cu]Cu-NOTA-抗PD-1和[Cu]Cu-NOTA-抗PD-L1的生物分布；（3）使用[Cu]Cu-NOTA-抗PD-L1对皮下和原位KRAS肿瘤进行成像，同时共同注射未标记的抗PD-L1作为阻断剂以及不注射。
[Cu]Cu-NOTA-抗PD-L1是一种有前景的成像探针。通过共同注射过量的未标记抗PD-L1，来自脾脏的[Cu]Cu-NOTA-抗PD-L1的背景信号显著降低，从而能够清晰描绘原位胰腺肿瘤。
共同注射未标记的抗PD-L1是原位胰腺癌模型中PD-L1表达PET成像的一种有用方法。
