Wang Jing, Hu Xinxin, Wang Yueqi, A Rong, Li Xiaoqian, Sun Ying, Guan Zhengqi, Li Xiaona, Wu Yongyi, Wang Jiannan, Zhao Fangyu, Liu Yang, Wang Hongbin, Yu Hong, Wang Tianyi, Zhu Mengyuan, Li Xinyu, Zhang Duoyi, Chen Wei, Han Zhaoguo, Sun Xilin
Department of Nuclear Medicine, the Fourth Affiliated Hospital of Harbin Medical University, Xiangan N Street, Songbei District, Harbin, 150028, Heilongjiang, China.
NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC) of Harbin Medical University, Harbin, Heilongjiang, China.
Eur J Nucl Med Mol Imaging. 2025 Jan;52(2):416-426. doi: 10.1007/s00259-024-06911-7. Epub 2024 Sep 19.
The T cell immunoglobulin and ITIM domain (TIGIT) blockade immunotherapy response is directly associated with individual differences of TIGIT expression on tumour-infiltrating lymphocytes (TILs) in tumour immune microenvironment (TIME) of non-small cell lung cancer (NSCLC). Here, we developed a TIGIT-targeted PET tracer to evaluate its feasibility in predicting immunotherapy efficacy, aiming to manage NSCLC patients accurately.
We synthesised a F-labeled TIGIT-targeted D-peptide, [F]TTDP, and investigated the specificity of [F]TTDP both to murine TIGIT and human TIGIT by a series of in vitro and in vivo assays. [F]TTDP PET imaging was performed in humanised immune system (HIS) mice models bearing NSCLC patient-derived xenografts (PDXs) to evaluate the predictive value of FDA-approved combination immunotherapy of atezolizumab plus tiragolumab. Lastly, rhesus macaque was applied for [F] TTDP PET to explore the tracer's in vivo distribution and translational potential in non-human primates.
[F]TTDP showed high specificity for both murine TIGIT and human TIGIT in vitro and in vivo. The HIS NSCLC PDX platform was successfully established for [F]TTDP PET imaging, and tumour uptake of [F]TTDP was significantly correlated with the TIGIT expression of TILs in the TIME. [F]TTDP PET imaging, in predicting treatment response to the combination immunotherapy in NSCLC HIS-PDX models, showed a sensitivity of 83.33% and a specificity of 100%. In addition, [F]TTDP PET also showed cross-species consistency of the tracer biodistribution between non-human primate and murine animals, and no adverse events were observed.
The combined implementation of the [F]TTDP and HIS-PDX model creates a state-of-the-art preclinical platform that will impact the identification and validation of TIGIT-targeted PET image-guided diagnosis, treatment response prediction, beneficial patient screening, novel immunotherapies, and ultimately the outcome of NSCLC patients. We first provided in vivo biodistribution of [F]TTDP PET imaging in rhesus macaque, indicating its excellent translational potential in the clinic.
T细胞免疫球蛋白和免疫受体酪氨酸抑制基序结构域（TIGIT）阻断免疫疗法的反应与非小细胞肺癌（NSCLC）肿瘤免疫微环境（TIME）中肿瘤浸润淋巴细胞（TILs）上TIGIT表达的个体差异直接相关。在此，我们开发了一种靶向TIGIT的PET示踪剂，以评估其在预测免疫疗法疗效方面的可行性，旨在准确管理NSCLC患者。
我们合成了一种F标记的靶向TIGIT的D肽，[F]TTDP，并通过一系列体外和体内试验研究了[F]TTDP对小鼠TIGIT和人类TIGIT的特异性。在携带NSCLC患者来源异种移植物（PDXs）的人源化免疫系统（HIS）小鼠模型中进行[F]TTDP PET成像，以评估FDA批准的阿替利珠单抗加替雷利珠单抗联合免疫疗法的预测价值。最后，将恒河猴应用于[F]TTDP PET，以探索该示踪剂在非人灵长类动物体内的分布及其转化潜力。
[F]TTDP在体外和体内对小鼠TIGIT和人类TIGIT均显示出高特异性。成功建立了用于[F]TTDP PET成像的HIS NSCLC PDX平台，[F]TTDP的肿瘤摄取与TIME中TILs的TIGIT表达显著相关。[F]TTDP PET成像在预测NSCLC HIS-PDX模型中联合免疫疗法的治疗反应时，显示出83.33%的敏感性和100%的特异性。此外，[F]TTDP PET还显示了该示踪剂在非人灵长类动物和小鼠之间生物分布的跨物种一致性，且未观察到不良事件。
[F]TTDP与HIS-PDX模型的联合应用创建了一个先进的临床前平台，这将影响靶向TIGIT的PET图像引导诊断的识别和验证、治疗反应预测、有益患者筛选、新型免疫疗法，并最终影响NSCLC患者的治疗结果。我们首次提供了[F]TTDP PET成像在恒河猴体内的生物分布情况，表明其在临床上具有出色的转化潜力。
