Galecto Biotech AB, Cobis Science Park, Ole Maaloes Vej 3, DK-2200 Copenhagen, Denmark.
Bioresearch and Veterinary Services, University of Edinburgh, The Chancellor's Building, 49 Little France Cresent, Edinburgh EH16 4SB, UK.
Int J Mol Sci. 2024 Nov 7;25(22):11948. doi: 10.3390/ijms252211948.
Galectin-1 is implicated in several pro-tumourigenic mechanisms and is considered immune-suppressive. The pharmacological inhibition of galectin-1 may be beneficial in cancers in which galectin-1 is overexpressed and driving cancer progression. This study aimed to further characterise the immunosuppressive cytokines influenced by galectin-1 in in vitro immune cell cultures and an in vivo inflammatory model using a recently discovered selective inhibitor of galectin-1, GB1908. To enable a translational approach and link mouse and human pharmacology, anti-CD3/anti-CD28 stimulated T cells cultured from human whole blood and mouse spleens were compared. For in vivo studies of T cell-mediated inflammation, the concanavalin-A (Con-A) mouse model was used to induce a T lymphocyte-driven acute liver injury phenotype. The inhibition of galectin-1 with GB1908 reduced IL-17A, IFNγ and TNFα in a concentration-dependent manner in both mouse and human T cells in vitro. The immunosuppressive cytokines measured in Con-A-treated mice were all upregulated compared to naïve mice. Subsequently, mice treated with GB1908 demonstrated a significant reduction in IL-17A, IFNγ, IL-6 and TNFα compared to vehicle-treated mice. In conclusion, galectin-1 induced the production of several important immune-suppressive cytokines from T cells in vitro and in vivo. This result suggests that, in the context of cancer therapy, a selective galectin-1 could be a viable approach as a monotherapy, or in combination with chemotherapeutic agents and/or checkpoint inhibitors, to enhance the numbers and activity of cytotoxic T cells in the tumour microenvironment of high galectin-1 expressing cancers.
半乳糖凝集素-1 参与了几种促肿瘤发生机制，并被认为具有免疫抑制作用。半乳糖凝集素-1 的药理学抑制可能对过度表达半乳糖凝集素-1并促进癌症进展的癌症有益。本研究旨在进一步研究在体外免疫细胞培养物和使用最近发现的半乳糖凝集素-1 选择性抑制剂 GB1908 的体内炎症模型中受半乳糖凝集素-1 影响的免疫抑制细胞因子。为了实现转化方法并将小鼠和人类药理学联系起来，比较了从人全血和小鼠脾脏培养的抗 CD3/抗 CD28 刺激的 T 细胞。为了研究 T 细胞介导的炎症的体内研究，使用伴刀豆球蛋白 A（Con-A）小鼠模型诱导 T 淋巴细胞驱动的急性肝损伤表型。GB1908 对半乳糖凝集素-1 的抑制以浓度依赖性方式减少了体外小鼠和人 T 细胞中 IL-17A、IFNγ 和 TNFα 的产生。与对照小鼠相比，在 Con-A 处理的小鼠中测量的免疫抑制细胞因子均上调。随后，与载体处理的小鼠相比，用 GB1908 处理的小鼠显示出 IL-17A、IFNγ、IL-6 和 TNFα 的显著减少。总之，半乳糖凝集素-1 在体外和体内诱导 T 细胞产生几种重要的免疫抑制细胞因子。这一结果表明，在癌症治疗的背景下，作为单一疗法或与化疗药物和/或检查点抑制剂联合使用，选择性半乳糖凝集素-1 可能是一种可行的方法，以增强高表达半乳糖凝集素-1 的癌症肿瘤微环境中细胞毒性 T 细胞的数量和活性。
