Stevenage Bioscience Catalyst, Galecto Biotech AB, Stevenage, United Kingdom.
Nine Edinburgh BioQuarter, Galecto Biotech AB, Edinburgh, United Kingdom.
Front Immunol. 2023 Aug 28;14:1250559. doi: 10.3389/fimmu.2023.1250559. eCollection 2023.
Galectin-3 (Gal-3) is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and has been suggested to predict a poor response to immune checkpoint therapy with the anti-PD-1 monoclonal antibody pembrolizumab. We aimed to assess if the effect of Gal-3 was a result of direct interaction with the immune checkpoint receptor.
The ability of Gal-3 to interact with the PD-1/PD-L1 complex in the absence and presence of blocking antibodies was assessed in biochemical and cellular assays as well as in an syngeneic mouse cancer model.
Gal-3 reduced the binding of the checkpoint inhibitors pembrolizumab (anti-PD-1) and atezolizumab (anti-PD-L1), by potentiating the interaction between the PD-1/PD-L1 complex. In the presence of a highly selective Gal-3 small molecule inhibitor (GB1211) the binding of the anti-PD-1/anti-PD-L1 therapeutics was restored to control levels. This was observed in both a surface plasmon resonance assay measuring protein-protein interactions and flow cytometry. Combination therapy with GB1211 and an anti-PD-L1 blocking antibody reduced tumor growth in an syngeneic model and increased the percentage of tumor infiltrating T lymphocytes.
Our study suggests that Gal-3 can potentiate the PD-1/PD-L1 immune axis and potentially contribute to the immunosuppressive signalling mechanisms within the tumor microenvironment. In addition, Gal-3 prevents atezolizumab and pembrolizumab target engagement with their respective immune checkpoint receptors. Reversal of this effect with the clinical candidate GB1211 offers a potential enhancing combination therapeutic with anti-PD-1 and -PD-L1 blocking antibodies.
半乳糖凝集素-3（Gal-3）是一种β-半乳糖苷结合凝集素，在侵袭性癌症的肿瘤微环境中高度表达，并被认为可预测抗 PD-1 单克隆抗体 pembrolizumab 免疫检查点治疗的反应不佳。我们旨在评估 Gal-3 的作用是否是与免疫检查点受体直接相互作用的结果。
在生化和细胞测定以及同种异体小鼠癌症模型中评估 Gal-3 在不存在和存在阻断抗体的情况下与 PD-1/PD-L1 复合物相互作用的能力。
Gal-3 通过增强 PD-1/PD-L1 复合物之间的相互作用，减少检查点抑制剂 pembrolizumab（抗 PD-1）和 atezolizumab（抗 PD-L1）的结合。在高选择性 Gal-3 小分子抑制剂（GB1211）存在的情况下，抗 PD-1/抗 PD-L1 治疗药物的结合恢复到对照水平。这在测量蛋白-蛋白相互作用的表面等离子体共振测定和流式细胞术上都观察到了。GB1211 与抗 PD-L1 阻断抗体联合治疗可减少同种异体模型中的肿瘤生长，并增加肿瘤浸润性 T 淋巴细胞的百分比。
我们的研究表明，Gal-3 可以增强 PD-1/PD-L1 免疫轴，并可能有助于肿瘤微环境中的免疫抑制信号机制。此外，Gal-3 阻止 atezolizumab 和 pembrolizumab 与其各自的免疫检查点受体结合。用临床候选物 GB1211 逆转这种效应提供了一种潜在的增强与抗 PD-1 和 -PD-L1 阻断抗体的联合治疗方法。
