LAG-3: from molecular functions to clinical applications
Tóm tắt
To prevent the destruction of tissues owing to excessive and/or inappropriate immune responses, immune cells are under strict check by various regulatory mechanisms at multiple points. Inhibitory coreceptors, including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against self-tissues and tumor cells. Immune checkpoint inhibitors that block PD-1 and CTLA-4 pathways significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment. However, response rates to such therapies are rather limited, and immune-related adverse events are also observed in a substantial patient population, leading to the urgent need for novel therapeutics with higher efficacy and lower toxicity. In addition to PD-1 and CTLA-4, a variety of stimulatory and inhibitory coreceptors are involved in the regulation of T cell activation. Such coreceptors are listed as potential drug targets, and the competition to develop novel immunotherapies targeting these coreceptors has been very fierce. Among such coreceptors, lymphocyte activation gene-3 (LAG-3) is expected as the foremost target next to PD-1 in the development of cancer therapy, and multiple clinical trials testing the efficacy of LAG-3-targeted therapy are underway. LAG-3 is a type I transmembrane protein with structural similarities to CD4. Accumulating evidence indicates that LAG-3 is an inhibitory coreceptor and plays pivotal roles in autoimmunity, tumor immunity, and anti-infection immunity. In this review, we summarize the current understanding of LAG-3, ranging from its discovery to clinical application.
Từ khóa
Tài liệu tham khảo
Andrews, 2019, Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups, Nat Immunol, 20, 1425, 10.1038/s41590-019-0512-0
Crise, 1992, Identification of palmitoylation sites on CD4, the human immunodeficiency virus receptor, J Biol Chem, 267, 13593, 10.1016/S0021-9258(18)42253-3
Annunziato, 1996, Expression and release of LAG‐3‐encoded protein by human CD4 + T cells are associated with IFN‐γ production, Faseb J, 10, 769, 10.1096/fasebj.10.7.8635694
Chen, 2015, Lymphocyte activation gene 3 negatively regulates the function of intrahepatic hepatitis C virus-specific CD8+ T cells, J Gastroenterol Hepatol, 30, 1788, 10.1111/jgh.13017
Roy, 2018, Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8+ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease, Front Immunol, 9, 10.3389/fimmu.2018.02922
Yang, 2017, Expression of LAG-3 defines exhaustion of intratumoral PD-1+ T cells and correlates with poor outcome in follicular lymphoma, Oncotarget, 8, 61425, 10.18632/oncotarget.18251
Zhang, 2017, LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes, Sci Immunol, 2, 10.1126/sciimmunol.aah4569
Lino, 2018, LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells, Immunity, 49, 120, 10.1016/j.immuni.2018.06.007
Chen, 2019, Nr4A transcription factors limit CAR T cell function in solid tumours, Nature, 567, 530, 10.1038/s41586-019-0985-x
Liu, 2019, Genome-Wide analysis identifies Nr4a1 as a key mediator of T cell dysfunction, Nature, 567, 525, 10.1038/s41586-019-0979-8
Wu, 2017, Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction, Immunity, 47, 1114, 10.1016/j.immuni.2017.11.003
Scott, 2019, Tox is a critical regulator of tumour-specific T cell differentiation, Nature, 571, 270, 10.1038/s41586-019-1324-y
Rudd, 2020, Small molecule inhibition of GSK-3 specifically inhibits the transcription of inhibitory co-receptor LAG-3 for enhanced anti-tumor immunity, Cell Rep, 30, 2075, 10.1016/j.celrep.2020.01.076
Mao, 2016, Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3, Science, 353, 10.1126/science.aah3374
Ruvolo, 2016, Galectin 3 as a guardian of the tumor microenvironment, Biochim Biophys Acta, 1863, 427, 10.1016/j.bbamcr.2015.08.008
Nishide, 2018, The role of semaphorins in immune responses and autoimmune rheumatic diseases, Nat Rev Rheumatol, 14, 19, 10.1038/nrrheum.2017.201
Takeda, 2017, Regulation of immune and neural function via leukocyte Ig-like receptors, J Biochem, 162, 73, 10.1093/jb/mvx036
Wei, 2015, Increased expression of immunosuppressive molecules on intratumoral and circulating regulatory T cells in non-small-cell lung cancer patients, Am J Cancer Res, 5, 2190
Chen, 2014, The effect of immune microenvironment on the progression and prognosis of colorectal cancer, Med Oncol, 31, 10.1007/s12032-014-0082-9
Deng, 2016, LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma, Oncoimmunology, 5, 10.1080/2162402X.2016.1239005
He, 2017, LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes, J Thorac Oncol, 12, 814, 10.1016/j.jtho.2017.01.019
Burugu, 2017, LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors, Ann Oncol, 28, 2977, 10.1093/annonc/mdx557
Keane, 2020, LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma, Blood Adv, 4, 1367, 10.1182/bloodadvances.2019001390
Que, 2019, LAG-3 expression on tumor-infiltrating T cells in soft tissue sarcoma correlates with poor survival, Cancer Biol Med, 16, 331, 10.20892/j.issn.2095-3941.2018.0306
Huang, 2015, LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model, Oncotarget, 6, 27359, 10.18632/oncotarget.4751
LaMotte-Mohs R , Shah K , Smith D , et al . MGD013, a bispecific PD-1 X LAG-3 dual affinity re-targeting (DART®) protein with T-cell immunomodulatory activity for cancer treatment. Cancer Res 2016;76.
Savitsky D , Ward R , Riordan C , et al . INCAGN02385 is an antagonist antibody targeting the co-inhibitory receptor LAG-3 for the treatment of human malignancies. Cancer Res 2018;78.
Zettl M , Wurm M , Schaaf O , et al . Characterization of the LAG-3 targeting antibody BI 754111 in monotherapy and in combination with the anti-PD-1 antibody RI 754091. Can Res 2018;78.
Ascierto P , Bono P , Bhatia S , et al . Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with PD-L1 therapy (MEL prior io) in all-comer and biomarker-enriched populations. Ann Oncol;217:v605–49.
Hong, 2018, Phase I/II study of LAG525 ± spartalizumab (PDR001) in patients (PTS) with advanced malignancies, JCO, 36, 10.1200/JCO.2018.36.15_suppl.3012
Avice, 1999, Lymphocyte activation gene-3, a MHC class II ligand expressed on activated T cells, stimulates TNF-alpha and IL-12 production by monocytes and dendritic cells, J Immunol, 162, 2748, 10.4049/jimmunol.162.5.2748