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LAG-3
Lymphocyte-activation gene 3
-
LAG-3 is an immune checkpoint receptor expressed on the surface of both activated cytotoxic T cells
and regulatory T cells (Tregs)
1-3
- One of the ligands for LAG-3 is the major histocompatibility complex (MHC), which presents antigen to T cells1-4
- The interaction of LAG-3 and MHC can negatively regulate
T-cell proliferation and the development of lasting memory T cells5
- As with programmed death receptor-1 (PD-1), repeated exposure to tumor antigen causes an increase in the presence and activity of LAG-3, leading to T-cell exhaustion6,7
- LAG-3 can be upregulated in cancer, which can result in negative signaling to immune cells, leading to T-cell exhaustion7,8
- Exhausted T cells have an impaired ability to fight tumor cells, which may result in tumor growth7
- T cells co-expressing both LAG-3 and PD-1 may show an even greater degree of exhaustion compared with those expressing LAG-3 alone9
- LAG-3 can also trigger the immunosuppressive activity of Tregs1
- In cancer, LAG-3–expressing Tregs gather at tumor sites and potently suppress cytotoxic T cells10
- Increased LAG-3 expression has been associated with poor prognosis in multiple tumor types3,11
- As shown in preclinical studies, PD-1 pathway blockade may upregulate LAG-3 to maintain tumor growth12
- Blockade of LAG-3 and other checkpoint pathways has been shown to enhance T-cell activity, leading to increased antitumor activity and limiting tumor burden in several preclinical studies13-15
How does LAG-3 suppress T-cell activity?
See how LAG-3 negatively regulates T-cell activation and proliferation
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REFERENCES–LAG-3
1. Huang CT, Workman CJ, Flies D, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21(4):503-513. 2. Baixeras E, Huard B, Miossec C, et al. Characterization of the lymphocyte activation gene 3–encoded protein: a new ligand for human leukocyte antigen class II antigens. J Exp Med. 1992;176(2):327-337. 3. Deng W-W, Mao L, Yu G-T, et al. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology. 2016;5(11):e1239005. doi:10.1080/2162402X.2016.1239005. 4. Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol. 1995;25(9):2718-2721. 5. Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali AA. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004;172(9):5450-5455. 6. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29-37. 7. Goding SR, Wilson KA, Xie Y, et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol. 2013;190(9):4899-4909. 8. Grosso JF, Kelleher CC, Harris TJ, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117(11):3383-3392. 9. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107(17):7875-7880. 10. Camisaschi C, Casati C, Rini F, et al. LAG-3 expression defines a subset of CD4+CD25highFoxp3+ regulatory T cells that are expanded at tumor sites. J Immunol. 2010;184(11):6545-6551. 11. Yang Z-Z, Kim HJ, Villasboas JC, et al. Expression of LAG-3 defines exhaustion of intratumoral PD-1+ T cells and correlates with poor outcome in follicular lymphoma. Oncotarget. 2017;8(37):61425-61439. 12. Huang R-Y, Francois A, McGray AJR, Miliotto A, Odunsi K. Compensatory upregulation of