377
Views
4
CrossRef citations to date
0
Altmetric
Review

LAG-3 is a promising inhibitory immune checkpoint for antitumor immunotherapy

ORCID Icon, , , , &
Pages 289-296 | Received 04 May 2021, Accepted 03 Feb 2022, Published online: 11 Feb 2022

References

  • Marin-Acevedo JA, Dholaria B, Soyano AE, et al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. 2018;11(1):39.
  • Goldberg MV, Drake CG. LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol. 2011;344:269–278.
  • Dong Y, Li X, Zhang L, et al. CD4(+) T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B. BMC Immunol. 2019;20(1):27.
  • Triebel F, Jitsukawa S, Baixeras E, et al., LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171(5):1393–1405.
  • Li N, Workman CJ, Martin SM, et al. Biochemical analysis of the regulatory T cell protein ly[phocyte activation gene-3 (LAG-3; CD223). J Immunol. 2004;173(11):6806–6812.
  • Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer. 2018;9(5–6):176–189.
  • Clayton KL, Douglas-Vail MB, Nur-ur Rahman AK, et al. Soluble T cell immunoglobulin mucin domain 3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression. J Virol. 2015;89(7):3723–3736.
  • Li N, Wang Y, Forbes K, et al. Metalloproteases regulate T-cell proliferation and effector function via LAG-3. Embo J. 2007;26(2):494–504.
  • Brignone C, Grygar C, Marcu M, et al. IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study. J Immune Based Ther Vaccines. 2007;5:5.
  • Buisson S, Triebel F. LAG-3 (CD223) reduces macrophage and dendritic cell differentiation from monocyte precursors. Immunology. 2005;114(3):369–374.
  • Delmastro MM, Styche AJ, Trucco MM, et al. Modulation of redox balance leaves murine diabetogenic TH1 T cells ”LAG-3-ing” behind. Diabetes. 2012;61(7):1760–1768.
  • Lienhardt C, Azzurri A, Amedei A, et al. Active tuberculosis in Africa is associated with reduced Th1 and increased Th2 activity in vivo. Eur J Immunol. 2002;32(6):1605–1613.
  • Brignone C, Gutierrez M, Mefti F, et al. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med. 2010;8:71.
  • Romano E, Michielin O, Voelter V, et al. MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial. J Transl Med. 2014;12:97.
  • Brignone C, Escudier B, Grygar C, et al. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009;15(19):6225–6231.
  • Triebel F, Hacene K, Pichon MF. A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors. Cancer Lett. 2006;235(1):147–153.
  • Yu X, Huang X, Chen X, et al. Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy. MAbs. 2019;11(6):1139–1148.
  • Xu F, Liu J, Liu D, et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 2014;74(13):3418–3428.
  • Dumic J, Dabelic S, Flögel M. Galectin-3: an open-ended story. Biochim Biophys Acta. 2006;1760(4):616–635.
  • Wood H. Parkinson disease: LAG3 facilitates cell-to-cell spread of α-synuclein pathology. Nat Rev Neurol. 2016;12(12):678.
  • Wang J, Sanmamed MF, Datar I, et al., Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell. 2019;176(1–2):334–347.e12.
  • Huard B, Mastrangeli R, Prigent P, et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc Natl Acad Sci U S A. 1997;94(11):5744–5749.
  • Huard B, Prigent P, Tournier M, et al. 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.
  • Weber S, Karjalainen K. Mouse CD4 binds MHC class II with extremely low affinity. Int Immunol. 1993;5(6):695–698.
  • Workman CJ, Dugger KJ, Vignali DA. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol. 2002;169(10):5392–5395.
  • Liu W, Tang L, Zhang G, et al. Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem. 2004;279(18):18748–18758.
  • Liu D, Lu Q, Wang X, et al. LSECtin on tumor-associated macrophages enhances breast cancer stemness via interaction with its receptor BTN3A3. Cell Res. 2019;29(5):365–378.
  • 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.
  • Kouo T, Huang L, Pucsek AB, et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res. 2015;3(4):412–423.
  • Guo M, Yuan F, Qi F, et al. Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8(+)T cells in hepatocellular carcinoma using multiplex quantitative analysis. J Transl Med. 2020;18(1):306.
  • Shahnawaz M, Mukherjee A, Pritzkow S, et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature. 2020;578(7794):273–277.
  • Cui SS, Du JJ, Liu SH, et al. Serum soluble lymphocyte activation gene-3 as a diagnostic biomarker in Parkinson’s disease: a pilot multicenter study. Mov Disord. 2019;34(1):138–141.
  • Iouzalen N, Andreae S, Hannier S, et al. LAP, a lymphocyte activation gene-3 (LAG-3)-associated protein that binds to a repeated EP motif in the intracellular region of LAG-3, may participate in the down-regulation of the CD3/TCR activation pathway. Eur J Immunol. 2001;31(10):2885–2891.
  • Maçon-Lemaître L, Triebel F. The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology. 2005;115(2):170–178.
  • Liang B, Workman C, Lee J, et al. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol. 2008;180(9):5916–5926.
  • Hemon P, Jean-Louis F, Ramgolam K, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol. 2011;186(9):5173–5183.
  • Maruhashi T, Okazaki IM, Sugiura D, et al., LAG-3 inhibits the activation of CD4(+) T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol. 2018;19(12):1415–1426.
  • He Y, Yu H, Rozeboom L, et al. 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. 2017;12(5):814–823.
  • Zhou H, Liu T, Wang Z. Analysis of non-small cell lung cancer microenvironment indicates preponderance of T cell exhaustion marker expression. Exp Cell Res. 2017;360(2):205–209.
  • 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.
  • Chen BJ, Dashnamoorthy R, Galera P, et al. The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma. Oncotarget. 2019;10(21):2030–2040.
  • Feng Y, Zhong M, Liu Y, et al. Expression of TIM-3 and LAG-3 in extranodal NK/T cell lymphoma, nasal type. Histol Histopathol. 2018;33(3):307–315.
  • Murga-Zamalloa CA, Brown NA, Wilcox RA. Expression of the checkpoint receptors LAG-3, TIM-3 and Vista in peripheral T cell lymphomas. J Clin Pathol. 2020;73(4):197–203.
  • Yang ZZ, Grote DM, Ziesmer SC, et al. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J Clin Invest. 2012;122(4):1271–1282.
  • Li F, Chen Y, Pang M, et al. Immune checkpoint inhibitors and cellular treatment for lymphoma immunotherapy. Clin Exp Immunol. 2021;205(1):1–11.
  • Ayodele O, Razak ARA. Immunotherapy in soft-tissue sarcoma. Curr Oncol. 2020;27(Suppl 1):17–23.
  • Yang Z, Zheng R, Zhang S, et al. Incidence, distribution of histological subtypes and primary sites of soft tissue sarcoma in China. Cancer Biol Med. 2019;16(3):565–574.
  • Que Y, Fang Z, Guan Y, et al. LAG-3 expression on tumor-infiltrating T cells in soft tissue sarcoma correlates with poor survival. Cancer Biol Med. 2019;16(2):331–340.
  • Li FJ, Zhang Y, Jin GX, et al. Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8(+) T cell in HCC patients. Immunol Lett. 2013;150(1–2):116–122.
  • Zhou G, Sprengers D, Boor PPC, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology. 2017;153(4):1107–1119.e10.
  • Demeure CE, Wolfers J, Martin-Garcia N, et al. T Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG-3): role of LAG-3/MHC class II interactions in cell-cell contacts. Eur J Cancer. 2001;37(13):1709–1718.
  • Giraldo NA, Becht E, Pagès F, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res. 2015;21(13):3031–3040.
  • Huang RY, Eppolito C, Lele S, et al. 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.
  • Huang RY, Francois A, McGray AR, et al. 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.
  • Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501.
  • Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175–2186.
  • Kwiatkowska D, Kluska P, Reich A. Beyond PD-1 immunotherapy in malignant melanoma. Dermatol Ther (Heidelb). 2019;9(2):243–257.
  • Bottai G, Raschioni C, Losurdo A, et al. An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers. Breast Cancer Res. 2016;18(1):121.
  • Burugu S, Gao D, Leung S, et al. LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors. Ann Oncol. 2017;28(12):2977–2984.
  • Wu S, Shi X, Wang J, et al. Triple-negative breast cancer: intact mismatch repair and partial co-expression of PD-L1 and LAG-3. Front Immunol. 2021;12:561793.
  • Su M, Huang CX, Dai AP. Immune checkpoint inhibitors: therapeutic tools for breast cancer. Asian Pac J Cancer Prev. 2016;17(3):905–910.
  • Andrews LP, Marciscano AE, Drake CG, et al. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017;276(1):80–96.
  • Shanghai. [Internet]. [cited 2021 Aug 29]. Available from: https://www.henlius.com/.
  • Zhejiang Province. [Internet]. [cited 2021 Aug 28]. Available from: https://db.dxy.cn/.
  • 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.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.