State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China.
Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, China.
Clin Cancer Res. 2022 Jul 1;28(13):2923-2937. doi: 10.1158/1078-0432.CCR-22-0159.
Efforts have been devoted to select eligible candidates for PD-1/PD-L1 immune checkpoint blocker (ICB) immunotherapy. Here, we have a serendipitous finding of positron emission tomography (PET) imaging tracer 2-[18F]FDG as a potential immunomodulator. Therefore, we hypothesize that 2-[18F]FDG could induce PD-L1 expression change and create an immune-favorable microenvironment for tumor immunotherapy.
We designed a series of assays to verify PD-L1 upregulation, and tested immunotherapy regimens based on 2-[18F]FDG and anti-PD-L1 mAb, as monotherapy and in combination, in fully immunocompetent mice of MC38 and CT26 models. PD-L1 expression and tumor microenvironment (TME) changes were analyzed by Western blot, transcriptomics study, and flow-cytometric analysis.
PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 2-[18F]FDG. The activation of NF-κB/IRF3 pathway and STAT1/3-IRF1 pathway play crucial parts in modulating PD-L1 expression after DNA damage and repair. Improved αPD-L1 mAb utilization rate and significant tumor growth delay were observed when the personalized therapeutic alliance of 2-[18F]FDG stimulation and ICB was used. In addition, combination of 2-[18F]FDG with αPD-L1 mAb could reprogram a TME from "cold" to "hot," to make low immunoactivity tumors sensitive to ICB therapy.
In summary, this promising paradigm has the potential to expand the traditional tumor theranostics. 2-[18F]FDG-based ICB immunotherapy is highly significant in enhancing antitumor effect. A research of 2-[18F]FDG-based ICB immunotherapy has been proposed to enhance the antitumor effect.
人们一直在努力筛选出适合接受 PD-1/PD-L1 免疫检查点抑制剂 (ICB) 免疫治疗的合格候选者。在这里，我们偶然发现正电子发射断层扫描 (PET) 成像示踪剂 2-[18F]FDG 可能是一种潜在的免疫调节剂。因此，我们假设 2-[18F]FDG 可以诱导 PD-L1 表达变化，并为肿瘤免疫治疗创造一个免疫有利的微环境。
我们设计了一系列实验来验证 PD-L1 的上调，并测试了基于 2-[18F]FDG 和抗 PD-L1 mAb 的免疫治疗方案，作为单药治疗和联合治疗，在完全免疫功能正常的 MC38 和 CT26 模型小鼠中进行。通过 Western blot、转录组学研究和流式细胞分析来分析 PD-L1 表达和肿瘤微环境 (TME) 的变化。
2-[18F]FDG 诱导后，PD-L1 呈时间和剂量依赖性上调。NF-κB/IRF3 通路和 STAT1/3-IRF1 通路的激活在 DNA 损伤和修复后调节 PD-L1 表达中起着至关重要的作用。当使用个性化的 2-[18F]FDG 刺激和 ICB 治疗联合治疗时，观察到 αPD-L1 mAb 利用率提高和肿瘤生长明显延迟。此外，2-[18F]FDG 与 αPD-L1 mAb 的联合使用可以将 TME 从“冷”重新编程为“热”，使低免疫活性的肿瘤对 ICB 治疗敏感。
总之，这一有前途的范例有可能扩展传统的肿瘤治疗学。基于 2-[18F]FDG 的 ICB 免疫疗法在增强抗肿瘤作用方面具有重要意义。提出了一项基于 2-[18F]FDG 的 ICB 免疫疗法的研究，以增强抗肿瘤效果。
