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LAG-3

Lymphocyte-activation gene 3 (LAG-3), an immune checkpoint receptor, can downregulate T-cell–mediated immune responses. Blockade of LAG-3 in combination with other checkpoint pathways may increase antitumor activity.

Expression and normal function

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 cells^1-4
The interaction of LAG-3 and MHC can negatively regulate T-cell proliferation and the development of lasting memory T cells ⁵

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 exhaustion^6,7

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Role in cancer

LAG-3 can be upregulated in cancer, which can result in negative signaling to immune cells, leading to T-cell exhaustion^7,8

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 types^3,11

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Preclinical evidence

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 studies^13-15

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1:13

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 PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2017;6(1):e1249561. doi:10.1080/2162402X.2016.1249561. 13. Wierz M, Pierson S, Guyonnet L, et al. Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood. 2018. doi:10.1182/blood-2017-06-792267. 14. Huang R-Y, Eppolito C, Lele S, Shrikant P, Matsuzaki J, Odunsi K. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget. 2015;6(29):27359-27377. 15. Lichtenegger FS, Rothe M, Schnorfeil FM, et al. Targeting LAG-3 and PD-1 to enhance T cell activation by antigen-presenting cells. Front Imunol. 2018;9:385. doi:10.3389/fimmu.2018.00385.