Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Antibody Therapeutics, Inc, Hayward, California, USA.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
J Biol Chem. 2022 Apr;298(4):101821. doi: 10.1016/j.jbc.2022.101821. Epub 2022 Mar 11.
Antibodies that target immune checkpoint proteins such as programmed cell death protein 1, programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 in human cancers have achieved impressive clinical success; however, a significant proportion of patients fail to respond to these treatments. Galectin-9 (Gal-9), a β-galactoside-binding protein, has been shown to induce T-cell death and facilitate immunosuppression in the tumor microenvironment by binding to immunomodulatory receptors such as T-cell immunoglobulin and mucin domain-containing molecule 3 and the innate immune receptor dectin-1, suggesting that it may have potential as a target for cancer immunotherapy. Here, we report the development of two novel Gal-9-neutralizing antibodies that specifically react with the N-carbohydrate-recognition domain of human Gal-9 with high affinity. We also show using cell-based functional assays that these antibodies efficiently protected human T cells from Gal-9-induced cell death. Notably, in a T-cell/tumor cell coculture assay of cytotoxicity, these antibodies significantly promoted T cell-mediated killing of tumor cells. Taken together, our findings demonstrate potent inhibition of human Gal-9 by neutralizing antibodies, which may open new avenues for cancer immunotherapy.
在人类癌症中，针对免疫检查点蛋白（如程序性细胞死亡蛋白 1、程序性死亡配体 1 和细胞毒性 T 淋巴细胞相关抗原 4 等）的抗体已经取得了令人瞩目的临床成功；然而，相当一部分患者对这些治疗方法没有反应。半乳糖凝集素-9（Gal-9）是一种β-半乳糖苷结合蛋白，通过与免疫调节受体（如 T 细胞免疫球蛋白和粘蛋白域包含分子 3 和先天免疫受体 dectin-1）结合，在肿瘤微环境中诱导 T 细胞死亡并促进免疫抑制，表明它可能具有作为癌症免疫治疗的靶标。在这里，我们报告了两种新型 Gal-9 中和抗体的开发，它们特异性地与高亲和力的人 Gal-9 的 N-糖基识别域反应。我们还通过基于细胞的功能测定表明，这些抗体有效地保护人 T 细胞免受 Gal-9 诱导的细胞死亡。值得注意的是，在 T 细胞/肿瘤细胞共培养的细胞毒性测定中，这些抗体显著促进了 T 细胞介导的肿瘤细胞杀伤。总之，我们的研究结果表明，中和抗体可以有效地抑制人 Gal-9，这可能为癌症免疫治疗开辟新的途径。
