Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA.
Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA; Division of Hematology-Oncology, UPMC Hillman Cancer Center, 5115 Centre Avenue, Pittsburgh, PA 15232, USA; Hematology/Oncology Fellowship Program, University of Pittsburgh Hillman Cancer Center, 5115 Centre Avenue, Pittsburgh, PA 15232, USA.
Semin Immunol. 2019 Apr;42:101305. doi: 10.1016/j.smim.2019.101305.
Immune checkpoint therapy has revolutionized cancer treatment by blocking inhibitory pathways in T cells that limits the an effective anti-tumor immune response. Therapeutics targeting CTLA-4 and PD1/PDL1 have progressed to first line therapy in multiple tumor types with some patients exhibiting tumor regression or remission. However, the majority of patients do not benefit from checkpoint therapy emphasizing the need for alternative therapeutic options. Lymphocyte Activation Gene 3 (LAG3) or CD223 is expressed on multiple cell types including CD4 and CD8 T cells, and T, and is required for optimal T cell regulation and homeostasis. Persistent antigen-stimulation in cancer or chronic infection leads to chronic LAG3 expression, promoting T cell exhaustion. Targeting LAG3 along with PD1 facilitates T cell reinvigoration. A substantial amount of pre-clinical data and mechanistic analysis has led to LAG3 being the third checkpoint to be targeted in the clinic with nearly a dozen therapeutics under investigation. In this review, we will discuss the structure, function and role of LAG3 in murine and human models of disease, including autoimmune and inflammatory diseases, chronic viral and parasitic infections, and cancer, emphasizing new advances in the development of LAG3-targeting immunotherapies for cancer that are currently in clinical trials.
免疫检查点疗法通过阻断 T 细胞中抑制性途径，限制有效的抗肿瘤免疫反应，从而彻底改变了癌症治疗。靶向 CTLA-4 和 PD1/PDL1 的治疗方法已经在多种肿瘤类型中进展为一线治疗，一些患者表现出肿瘤消退或缓解。然而，大多数患者并未从检查点治疗中获益，这强调了需要替代治疗选择。淋巴细胞激活基因 3（LAG3）或 CD223 表达于多种细胞类型，包括 CD4 和 CD8 T 细胞和 T 细胞，对于最佳 T 细胞调节和稳态是必需的。在癌症或慢性感染中持续的抗原刺激导致慢性 LAG3 表达，促进 T 细胞衰竭。靶向 LAG3 与 PD1 一起促进 T 细胞再激活。大量的临床前数据和机制分析导致 LAG3 成为在临床中被靶向的第三个检查点，目前有十几个治疗药物正在研究中。在这篇综述中，我们将讨论 LAG3 在疾病的鼠和人类模型中的结构、功能和作用，包括自身免疫和炎症性疾病、慢性病毒和寄生虫感染以及癌症，并强调目前正在临床试验中的针对癌症的 LAG3 靶向免疫疗法的新进展。
