Pezzana Stefania, Blaess Simone, Traenkle Bjoern, Schaefer Anna, Ruoff Lara, Tako Bredi, Castaneda Vega Salvador, Kaiser Philipp D, Wagner Teresa, Gonzalez-Menendez Irene, Quintanilla-Martinez Leticia, Rochwarger Alexander, Schürch Christian M, Riel Simon, Schaller Martin, van Genugten Evelien A J, van der Hoorn Iris A E, Gorris Mark A J, Steinvoort Megan, Peeters Eva, de Vries I Jolanda M, van den Heuvel Michel M, Aarntzen Erik H J G, Maurer Andreas, Rothbauer Ulrich, Pichler Bernd J, Kneilling Manfred, Sonanini Dominik
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tuebingen, University of Tuebingen, Tuebingen, Germany.
NMI Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, Germany.
Sci Adv. 2025 Jun 27;11(26):eadw1924. doi: 10.1126/sciadv.adw1924. Epub 2025 Jun 25.
CD4 T cells are crucial in shaping response and resistance to immunotherapy. To enhance our understanding of their multifaceted functions, we developed copper-64-radiolabeled nanobodies targeting the human CD4 receptor (Cu-CD4-Nb1) for positron emission tomography (PET). In human CD4-receptor knock-in mice, Cu-CD4-Nb1 specifically accumulated in different orthotopic tumors, correlating with histological CD4 cell densities. Based on intratumoral CD4 cell distribution patterns within the core and periphery, we distinguished responders to combined αPD-1/4-1BB antibodies early on-treatment. CD4-PET identified resistance to αPD-1 monotherapy, which was mitigated by adding regulatory T cell-depleting α4-1BB antibodies. Patients with early-stage non-small cell lung cancer who relapsed after neoadjuvant αPD-L1 therapy revealed low CD4 T cell densities in the tumor core. In human and mouse tumor tissues, regulatory T cells correlated with CD4 cell densities. Thus, visualizing the spatial distribution patterns of CD4 cells by PET offers mechanistic insights into CD4-mediated therapy efficacy, with great potential for guiding combinatorial immunotherapies in patients with cancer.
CD4 T细胞在塑造对免疫疗法的反应和抗性方面至关重要。为了加深我们对其多方面功能的理解，我们开发了用于正电子发射断层扫描（PET）的靶向人CD4受体的铜-64放射性标记纳米抗体（Cu-CD4-Nb1）。在人CD4受体敲入小鼠中，Cu-CD4-Nb1特异性积聚在不同的原位肿瘤中，与组织学CD4细胞密度相关。基于肿瘤核心和周边内的肿瘤内CD4细胞分布模式，我们在联合αPD-1/4-1BB抗体治疗早期就区分出反应者。CD4-PET确定了对αPD-1单药治疗的抗性，通过添加消耗调节性T细胞的α4-1BB抗体可减轻这种抗性。新辅助αPD-L1治疗后复发的早期非小细胞肺癌患者在肿瘤核心显示出低CD4 T细胞密度。在人和小鼠肿瘤组织中，调节性T细胞与CD4细胞密度相关。因此，通过PET可视化CD4细胞的空间分布模式为CD4介导的治疗疗效提供了机制性见解，在指导癌症患者的联合免疫疗法方面具有巨大潜力。
