Laboratory of Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Oncology, Merck & Co., Inc., Rahway, NJ, United States.
Front Immunol. 2024 Aug 21;15:1444424. doi: 10.3389/fimmu.2024.1444424. eCollection 2024.
Lymphocyte activation gene (Lag)-3 is an inhibitory co-receptor and target of immune checkpoint inhibitor (ICI) therapy for cancer. The dynamic behavior of Lag-3 was analyzed at the immune synapse upon T-cell activation to elucidate the Lag-3 inhibitory mechanism. Lag-3 formed clusters and co-localized with T-cell receptor microcluster (TCR-MC) upon T-cell activation similar to PD-1. Lag-3 blocking antibodies (Abs) inhibited the co-localization between Lag-3 and TCR-MC without inhibiting Lag-3 cluster formation. Lag-3 also inhibited MHC-II-independent stimulation and Lag-3 Ab, which did not block MHC-II binding could still block Lag-3's inhibitory function, suggesting that the Lag-3 Ab blocks the Lag-3 inhibitory signal by dissociating the co-assembly of TCR-MC and Lag-3 clusters. Consistent with the combination benefit of PD-1 and Lag-3 Abs to augment T-cell responses, bispecific Lag-3/PD-1 antagonists effectively inhibited both cluster formation and co-localization of PD-1 and Lag-3 with TCR-MC. Therefore, Lag-3 inhibits T-cell activation at TCR-MC, and the target of Lag-3 ICI is to dissociate the co-localization of Lag-3 with TCR-MC.
淋巴细胞激活基因 (Lag)-3 是一种抑制性共受体，也是癌症免疫检查点抑制剂 (ICI) 治疗的靶点。在 T 细胞激活时，在免疫突触上分析了 Lag-3 的动态行为，以阐明 Lag-3 的抑制机制。Lag-3 在 T 细胞激活时与 T 细胞受体微簇 (TCR-MC) 形成簇并共定位，类似于 PD-1。Lag-3 阻断抗体 (Abs) 抑制了 Lag-3 和 TCR-MC 之间的共定位，而不抑制 Lag-3 簇的形成。Lag-3 还抑制 MHC-II 非依赖性刺激，并且不阻断 MHC-II 结合的 Lag-3 Ab 仍可阻断 Lag-3 的抑制功能，表明 Lag-3 Ab 通过解离 TCR-MC 和 Lag-3 簇的共组装来阻断 Lag-3 的抑制信号。与 PD-1 和 Lag-3 Abs 联合增强 T 细胞反应的结合益处一致，双特异性 Lag-3/PD-1 拮抗剂有效抑制了 PD-1 和 Lag-3 与 TCR-MC 的簇形成和共定位。因此，Lag-3 在 TCR-MC 处抑制 T 细胞激活，Lag-3 ICI 的靶点是解离 Lag-3 与 TCR-MC 的共定位。
