免疫检查点抑制剂（ICI）彻底改变了转移性恶性黑色素瘤（MM）的治疗并提高了长期生存率。尽管取得了令人印象深刻的结果，但一些患者仍然患有进展性疾病，并且正在寻找预测 ICI 治疗反应的生物标志物。在这项研究中，半乳糖凝集素 3 (Gal-3) 被认为是一种感兴趣的分子，既可以作为治疗反应的标志物，也可以作为增强 ICI 治疗的治疗靶点。我们之前已经证明了程序性细胞死亡 1 (PD-1) 和 Gal-3 之间的结合，在这里，我们研究了转移性 MM 患者中 PD-1、pembrolizumab 和 Gal-3 之间的相互作用。PD-1 之间的结合、pembrolizumab 和 Gal-3 通过表面等离子共振 (SPR) 和低温电子显微镜 (cryo-EM) 进行研究。在体外培养物中研究了该功能，并在接受派姆单抗治疗的转移性多发性骨髓瘤患者中测量了 PD-1 和 Gal-3 的可溶性水平。通过 SPR，我们证明 Gal-3 可以阻断 PD-1 和派姆单抗之间的结合，并使用冷冻电镜进一步可视化空间抑制。用 Gal-3 培养的 T 细胞减少了促炎细胞因子的产生，而帕博利珠单抗无法挽救这种情况。在转移性多发性骨髓瘤患者中，研究期间无进展生存期较长的患者血浆中 Gal-3 水平高，而疾病进展患者肿瘤中 Gal-3 表达高。帕博利珠单抗治疗后血浆中可溶性 PD-1 水平增加，并与疾病进展相关。我们证明 PD-1 和 Gal-3 之间的相互作用会干扰帕博利珠单抗的结合，支持 Gal-3 在pembrolizumab 无法挽救肿瘤微环境。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic malignant melanoma (MM) and improved long-term survival. Despite the impressive results, some patients still have progressive disease, and the search for biomarkers predicting response to ICI treatment is ongoing. In this search, galectin-3 (Gal-3) has been suggested as a molecule of interest, both as a marker of treatment response and as a treatment target to potentiate ICI therapy. We have previously demonstrated the binding between programmed cell death 1 (PD-1) and Gal-3, and here, we investigated the interaction between PD-1, pembrolizumab, and Gal-3 in metastatic MM patients.The binding between PD-1, pembrolizumab and Gal-3 was investigated by surface plasmon resonance (SPR) and cryogenic electron microscopy (cryo-EM). The function was studied in in vitro cultures and soluble levels of both PD-1 and Gal-3 were measured in metastatic MM patients, treated with pembrolizumab.By SPR, we demonstrated that Gal-3 can block the binding between PD-1 and pembrolizumab, and further visualized a steric inhibition using cryo-EM. T cells cultured with Gal-3 had reduced pro-inflammatory cytokine production, which could not be rescued by pembrolizumab. In patients with metastatic MM, high levels of Gal-3 in plasma were found in patients with a longer progression-free survival in the study period, whereas high Gal-3 expression in the tumor was seen in patients with disease progression. Soluble PD-1 levels in plasma increased after treatment with pembrolizumab and correlated with disease progression.We demonstrate that the interaction between PD-1 and Gal-3 interferes with the binding of pembrolizumab, supporting that an immune suppression induced by Gal-3 in the tumor microenvironment cannot be rescued by pembrolizumab.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.