Lauwers Yoline, De Groof Timo W M, Vincke Cécile, Van Craenenbroeck Jolien, Jumapili Neema Ahishakiye, Barthelmess Romina Mora, Courtoy Guillaume, Waelput Wim, De Pauw Tessa, Raes Geert, Devoogdt Nick, Van Ginderachter Jo A
Molecular Imaging and Therapy Research Group, Vrije Universiteit Brussel, Brussels 1090, Belgium.
Laboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Center for Inflammation Research, Brussels 1050, Belgium.
Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2409668121. doi: 10.1073/pnas.2409668121. Epub 2024 Dec 18.
Immunotherapies have emerged as an effective treatment option for immune-related diseases, such as cancer and inflammatory diseases. However, variations in patient responsiveness limit the broad applicability and success of these immunotherapies. Noninvasive whole-body imaging of the immune status of individual patients during immunotherapy could enable the prediction and monitoring of the patient's response, resulting in more personalized treatments. In this study, we developed a nanobody-based immunotracer targeting CD163, a receptor specifically expressed on macrophages. This anti-CD163 immunotracer bound to human and mouse CD163 with high affinity and specificity without competing for ligand binding. Furthermore, the tracer showed no unwanted immune cell activation and was nonimmunogenic. Upon radiolabeling of the anti-CD163 immunotracer, specific imaging of CD163 macrophages using micro-single-photon emission computerized tomography/computed tomography or micro-positron emission tomography/CT was performed. The anti-CD163 immunotracer was able to stratify immunotherapy responders from nonresponders (NR) by visualizing differences in the intratumoral CD163 TAM distribution in Lewis lung carcinoma-ovalbumin tumor-bearing mice receiving an anti-programmed cell death protein-1 (PD-1)/CSF1R combination treatment. Immunotherapy-responding mice showed a more homogeneous distribution of the PET signal in the middle of the tumor, while CD163 TAMs were located at the tumor periphery in NR. As such, visualization of CD163 TAM distribution in the tumor microenvironment could allow a prediction or follow-up of therapy response. Altogether, this study describes an immunotracer, specific for CD163 macrophages, that allows same-day imaging and follow-up of these immune cells in the tumor microenvironment, providing a good basis for the prediction and follow-up of immunotherapy responses in cancer patients.
免疫疗法已成为治疗免疫相关疾病（如癌症和炎症性疾病）的有效选择。然而，患者反应的差异限制了这些免疫疗法的广泛适用性和成功率。在免疫治疗期间对个体患者的免疫状态进行无创全身成像可以预测和监测患者的反应，从而实现更个性化的治疗。在本研究中，我们开发了一种基于纳米抗体的免疫示踪剂，靶向CD163，这是一种在巨噬细胞上特异性表达的受体。这种抗CD163免疫示踪剂以高亲和力和特异性与人及小鼠CD163结合，且不竞争配体结合。此外，该示踪剂未显示出不必要的免疫细胞激活，且无免疫原性。在对抗CD163免疫示踪剂进行放射性标记后，使用微型单光子发射计算机断层扫描/计算机断层扫描或微型正电子发射断层扫描/CT对CD163巨噬细胞进行了特异性成像。抗CD163免疫示踪剂能够通过可视化接受抗程序性细胞死亡蛋白1（PD-1）/CSF1R联合治疗的携带Lewis肺癌-卵清蛋白肿瘤的小鼠肿瘤内CD163肿瘤相关巨噬细胞（TAM）分布的差异，将免疫治疗反应者与无反应者（NR）区分开来。免疫治疗有反应的小鼠在肿瘤中部的PET信号分布更均匀，而NR小鼠的CD163 TAM位于肿瘤周边。因此，可视化肿瘤微环境中CD163 TAM的分布可以预测或随访治疗反应。总之，本研究描述了一种对CD163巨噬细胞具有特异性的免疫示踪剂，可在同一天对肿瘤微环境中的这些免疫细胞进行成像和随访，为预测和随访癌症患者的免疫治疗反应提供了良好的基础。
