Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

LAG-3 as the third checkpoint inhibitor

Nature Immunology volume 24, pages 1415–1422 (2023)Cite this article

Subjects

Abstract

Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that is highly expressed by exhausted T cells. LAG-3 is a promising immunotherapeutic target, with more than 20 LAG-3-targeting therapeutics in clinical trials and a fixed-dose combination of anti-LAG-3 and anti-PD-1 now approved to treat unresectable or metastatic melanoma. Although LAG-3 is widely recognized as a potent inhibitory receptor, important questions regarding its biology and mechanism of action remain. In this Perspective, we focus on gaps in the understanding of LAG-3 biology and discuss the five biggest topics of current debate and focus regarding LAG-3, including its ligands, signaling and mechanism of action, its cell-specific functions, its importance in different disease settings, and the development of novel therapeutics.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: LAG-3 ligands.
Fig. 2: LAG-3 signaling.
Fig. 3: LAG-3-specific therapeutics.

References

  1. Triebel, F. et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 171, 1393–1405 (1990). This study describes LAG-3.

    Article  CAS  PubMed  Google Scholar 

  2. Huard, B., Gaulard, P., Faure, F., Hercend, T. & Triebel, F. Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand. Immunogenetics 39, 213–217 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Kisielow, M., Kisielow, J., Capoferri-Sollami, G. & Karjalainen, K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur. J. Immunol. 35, 2081–2088 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Workman, C. J. et al. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J. Immunol. 182, 1885–1891 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Workman, C. J., Rice, D. S., Dugger, K. J., Kurschner, C. & Vignali, D. A. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur. J. Immunol. 32, 2255–2263 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Workman, C. J. & Vignali, D. A. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur. J. Immunol. 33, 970–979 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Workman, C. J., Dugger, K. J. & Vignali, D. A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J. Immunol. 169, 5392–5395 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Tawbi, H. A. et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N. Engl. J. Med. 386, 24–34 (2022). The study reports the efficacy and safety of a phase 2/3 clinical trial of a relatlimab and nivolumab in patients with metastatic or unresectable melanoma. This combination resulted in 47.7% PFS in comparison to 36% PFS with nivolumab single therapy. No new safety signals with this combination therapy were reported.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. US Food and Drug Administration. FDA approves Opdualag for unresectable or metastatic melanoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-opdualag-unresectable-or-metastatic-melanoma (2022).

  10. Hodi, F. S. et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 19, 1480–1492 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Long, G. V. et al. Overall survival and response with nivolumab and relatlimab in advanced melanoma. N. Engl. J. Med. 2, 4 (2023).

  12. Ascierto, P. A. et al. Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1/programmed death ligand 1 therapy: results from the phase I/IIa RELATIVITY-020 trial. J. Clin. Oncol. 41, 2724–2735 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Maruhashi, T. et al. Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity. Immunity 55, 912–924 (2022). This study highlights MHC class II as a critical functional ligand of LAG-3 in mouse models of autoimmunity and cancer.

  14. Huard, B. et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc. Natl Acad. Sci. USA 94, 5744–5749 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Maruhashi, T. et al. LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat. Immunol. 19, 1415–1426 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Baixeras, E. et al. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J. Exp. Med. 176, 327–337 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Kouo, T. 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. 3, 412–423 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Friedman, L. A., Ring, K. L. & Mills, A. M. LAG-3 and GAL-3 in endometrial carcinoma: emerging candidates for immunotherapy. Int. J. Gynecol. Pathol. 39, 203–212 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Cocks, M. M. & Mills, A. M. The immune checkpoint inhibitor LAG-3 and its ligand GAL-3 in vulvar squamous neoplasia. Int. J. Gynecol. Pathol. 41, 113–121 (2022).

    Article  CAS  PubMed  Google Scholar 

  20. Bae, J. et al. Targeting LAG-3/GAL-3 to overcome immunosuppression and enhance antitumor immune responses in multiple myeloma. Leukemia 36, 138–154 (2022).

    Article  CAS  PubMed  Google Scholar 

  21. Xu, F. et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T cell responses. Cancer Res. 74, 3418–3428 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Shi, A. P. et al. Immune checkpoint LAG-3 and its ligand FGL1 in cancer. Front. Immunol. 12, 785091 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Wang, J. et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176, 334–347 (2019). FGL1 was demonstrated to be the major functional ligand for LAG-3 independently of its canonical ligand MHC class II. FGL1 was shown to inhibit antigen-specific T cell activation, and deletion of FGL1 promoted T cell immunity.

    Article  CAS  PubMed  Google Scholar 

  24. Ming, Q. et al. LAG-3 ectodomain structure reveals functional interfaces for ligand and antibody recognition. Nat. Immunol. 23, 1031–1041 (2022). This study reports the structure of LAG-3. The human and mouse LAG-3 ectodomains were identified as dimers via the D2 domain. The binding sites for FGL1 and MHC class II were infered to occur via the flexible loop 2 region in the LAG-3 D1 domain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li, N., Workman, C. J., Martin, S. M. & Vignali, D. A. Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223). J. Immunol. 173, 6806–6812 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Guy, C. et al. LAG-3 associates with TCR–CD3 complexes and suppresses signaling by driving co-receptor–Lck dissociation. Nat. Immunol. 23, 757–767 (2022). This study provides clear mechanistic insight into the inhibitory function of LAG-3. It shows that LAG-3 could function independently of MHC class II and could instead use the TCR–CD3 complex as a ligand in cis within the immunological synapse. This led to dissociation of Lck from CD4 and CD8 co-receptors, resulting in reduced TCR signaling. This mechanism provides insight for the design of LAG-3-targeting immunotherapies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mao, X. et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016). This study demonstrates that neuron-to-neuron transmission of pathological alpha-synuclein is mediated by binding to LAG-3 via endocytosis of α-synPFF in Parkinson’s disease. Identification of α-synPFF as a ligand for LAG-3 provides new opportunities for targeting α-synucleinopathies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Emmenegger, M. et al. LAG-3 is not expressed in human and murine neurons and does not modulate alpha-synucleinopathies. EMBO Mol. Med. 13, e14745 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maeda, T. K., Sugiura, D., Okazaki, I. M., Maruhashi, T. & Okazaki, T. Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J. Biol. Chem. 294, 6017–6026 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Iouzalen, N., Andreae, S., Hannier, S. & Triebel, F. 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 downregulation of the CD3/TCR activation pathway. Eur. J. Immunol. 31, 2885–2891 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Zhang, S. et al. Mechanistic basis for receptor-mediated pathological alpha-synuclein fibril cell-to-cell transmission in Parkinson’s disease. Proc. Natl Acad. Sci. USA 118, e2011196118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Freeze, B., Acosta, D., Pandya, S., Zhao, Y. & Raj, A. Regional expression of genes mediating trans-synaptic alpha-synuclein transfer predicts regional atrophy in Parkinson disease. Neuroimage Clin. 18, 456–466 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Gu, H. et al. Lymphocyte activation gene 3 (LAG-3) contributes to alpha-synucleinopathy in alpha-synuclein transgenic mice. Front. Cell Neurosci. 15, 656426 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, N. et al. Metalloproteases regulate T cell proliferation and effector function via LAG-3. EMBO J. 26, 494–504 (2007). This study shows that LAG-3 surface expression is controlled by two metalloproteases: ADAM10 and ADAM17. This shedding affected the inhibitory effect of LAG-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Andrews, L. P. et al. Resistance to PD-1 blockade in the absence of metalloprotease-mediated LAG-3 shedding. Sci. Immunol. 5, eabc2728 (2020). This study showed that expression of non-sheddable LAG-3 on CD4+ T cells limits the therapeutic efficacy of anti-PD-1 in a mouse model of cancer. Furthermore, analysis of patient samples highlighted the inverse correlation between surface LAG-3 expression and ADAM10 expression, and that high LAG-3 and low ADAM10 correlated with poor patient prognosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Andrews, L. P. et al. A Cre-driven allele-conditioning line to interrogate CD4+ conventional T cells. Immunity 54, 2209–2217 (2021).

    Article  CAS  PubMed  Google Scholar 

  37. Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Grosso, J. F. et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J. Immunol. 182, 6659–6669 (2009). This study shows that the combinatorial targeting of LAG-3 and PD-1 promoted sterilizing immunity against a chronic viral infection.

    Article  CAS  PubMed  Google Scholar 

  39. Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012). This study shows that the combinatorial targeting of LAG-3 and PD-1 had synergistic antitumor activity, leading to the clinical development of LAG-3 therapeutics for the treatment of cancer.

    Article  CAS  PubMed  Google Scholar 

  40. Dadey, R. E., Workman, C. J. & Vignali, D. A. A. Regulatory T cells in the tumor microenvironment. Adv. Exp. Med. Biol. 1273, 105–134 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. Do, J. S. et al. An IL-27/LAG-3 axis enhances Foxp3+ regulatory T cell-suppressive function and therapeutic efficacy. Mucosal Immunol. 9, 137–145 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Overacre-Delgoffe, A. E. & Vignali, D. A. A. Treg fragility: a prerequisite for effective antitumor immunity? Cancer Immunol. Res. 6, 882–887 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gagliani, N. et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19, 739–746 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Andrews, L. P., Marciscano, A. E., Drake, C. G. & Vignali, D. A. LAG-3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 276, 80–96 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Zhang, Q. et al. LAG-3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci. Immunol. 2, eaah4569 (2017).

  47. Okamura, T. et al. CD4+CD25−LAG-3+ regulatory T cells controlled by the transcription factor Egr-2. Proc. Natl Acad. Sci. USA 106, 13974–13979 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Okamura, T. et al. TGF-β3-expressing CD4+CD25−LAG-3+ regulatory T cells control humoral immune responses. Nat. Commun. 6, 6329 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Huang, W., Solouki, S., Carter, C., Zheng, S. G. & August, A. Beyond type 1 regulatory T cells: coexpression of LAG-3 and CD49b in IL-10-producing T cell lineages. Front. Immunol. 9, 2625 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Lino, A. C. et al. LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells. Immunity 49, 120–133 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Castelli, C., Triebel, F., Rivoltini, L. & Camisaschi, C. Lymphocyte activation gene-3 (LAG-3, CD223) in plasmacytoid dendritic cells (pDCs): a molecular target for the restoration of active antitumor immunity. Oncoimmunology 3, e967146 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yang, L. L. et al. pDC depletion induced by CD317 blockade drives the antitumor immune response in head and neck squamous cell carcinoma. Oral Oncol. 96, 131–139 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Grebinoski, S. & Vignali, D. A. Inhibitory receptor agonists: the future of autoimmune disease therapeutics? Curr. Opin. Immunol. 67, 1–9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Grebinoski, S. et al. Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG-3. Nat. Immunol. 23, 868–877 (2022). Intra-islet CD8+ T cells in autoimmune diabetes have phenotypic, transcriptional, metabolic and epigenetic characteristics of exhausted T cells identified as the ‘restrained’ phenotype. CD8+ T cell–restricted deletion of LAG-3 perturbs the ‘restrained’ phenotype and accelerates disease phenotype, implicating LAG-3 as a target for autoimmune therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu, Y., Sorce, S., Nuvolone, M., Domange, J. & Aguzzi, A. Lymphocyte activation gene 3 (LAG-3) expression is increased in prion infections but does not modify disease progression. Sci. Rep. 8, 14600 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Okazaki, T. et al. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J. Exp. Med. 208, 395–407 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bettini, M. et al. Cutting edge: accelerated autoimmune diabetes in the absence of LAG-3. J. Immunol. 187, 3493–3498 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Matsuzaki, J. 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. USA 107, 7875–7880 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Deng, W. W. et al. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology 5, e1239005 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Guo, M. 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. 18, 306 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Clements, D. M. et al. Phenotypic and functional analyses guiding combination immune checkpoint immunotherapeutic strategies in HTLV-1 infection. Front. Immunol. 12, 608890 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen, N. et al. Lymphocyte activation gene 3 negatively regulates the function of intrahepatic hepatitis C virus-specific CD8+ T cells. J. Gastroenterol. Hepatol. 30, 1788–1795 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Dong, Y. 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. 20, 27 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Zhang, J. et al. Elevated LAG-3 on CD4+ T cells negatively correlates with neutralizing antibody response during HCV infection. Immunol. Lett. 212, 46–52 (2019).

    Article  CAS  PubMed  Google Scholar 

  66. Ma, Q. Y., Huang, D. Y., Zhang, H. J., Wang, S. & Chen, X. F. Function and regulation of LAG-3 on CD4+CD25− T cells in non-small cell lung cancer. Exp. Cell. Res. 360, 358–364 (2017).

    Article  CAS  PubMed  Google Scholar 

  67. Datar, I. et al. Expression analysis and significance of PD-1, LAG-3 and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin. Cancer Res. 25, 4663–4673 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Juno, J. A. et al. Elevated expression of LAG-3, but not PD-1, is associated with impaired iNKT cytokine production during chronic HIV-1 infection and treatment. Retrovirology 12, 17 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Kotaskova, J. et al. High expression of lymphocyte-activation gene 3 (LAG-3) in chronic lymphocytic leukemia cells is associated with unmutated immunoglobulin variable heavy chain region (IGHV) gene and reduced treatment-free survival. J. Mol. Diagn. 12, 328–334 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Huang, R. Y. et al. LAG-3 and PD-1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget 6, 27359–27377 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Tilstra, J. S. et al. Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted. J. Clin. Invest. 128, 4884–4897 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Nakachi, S. et al. Interleukin-10-producing LAG-3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis. Arthritis Res. Ther. 19, 97 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Chen, S. Y., Hsu, W. T., Chen, Y. L., Chien, C. H. & Chiang, B. L. Lymphocyte-activation gene 3+ (LAG-3+) forkhead box protein 3− (FOXP3−) regulatory T cells induced by B cells alleviates joint inflammation in collagen-induced arthritis. J. Autoimmun. 68, 75–85 (2016).

    Article  CAS  PubMed  Google Scholar 

  74. Chu, K. H., Lin, S. Y. & Chiang, B. L. STAT6 pathway is critical for the induction and function of regulatory T cells induced by mucosal B cells. Front. Immunol. 11, 615868 (2020).

    Article  CAS  PubMed  Google Scholar 

  75. Morita, K. et al. Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production. Proc. Natl Acad. Sci. USA 113, E8131–E8140 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hivroz, C. LAG-3 disrupts the TCR signal by local acidification. Nat. Immunol. 23, 649–651 (2022).

    Article  CAS  PubMed  Google Scholar 

  77. Mullard, A. LAG-3 pushes immuno-oncology’s leading edge. Nat. Rev. Drug Discov. 21, 167–169 (2022).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the members of the D.A.A.V. laboratory (https://www.vignali-lab.com/) for discussions and critically reading the manuscript. Figures were created using BioRender.com licensed to University of Pittsburgh. This study was supported by the US National Institutes of Health (P01 AI108545 and R01 AI144422 to D.A.A.V).

Author information

Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Vaishali Aggarwal, Creg J. Workman & Dario A. A. Vignali

  2. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Vaishali Aggarwal, Creg J. Workman & Dario A. A. Vignali

  3. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Dario A. A. Vignali

Authors
  1. Vaishali Aggarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Creg J. Workman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dario A. A. Vignali
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

V.A., C.J.W. and D.A.A.V. conceptualized the outline of the Perspective. V.A. wrote the manuscript and designed the figures. C.J.W. and D.A.A.V. supervised, reviewed and revised the manuscript and figures. All authors read and approved the final manuscript draft.

Corresponding author

Correspondence to Dario A. A. Vignali.

Ethics declarations

Competing interests

D.A.A.V. and C.J.W. declare patents covering LAG-3, with others pending, and are entitled to a share in net income generated from licensing of these patent rights for commercial development. D.A.A.V. is a cofounder and stock holder of Novasenta, Potenza, Tizona and Trishula and a stock holder of Oncorus and Werewolf; has patents licensed and royalties in BMS and Novasenta; is a scientific advisory board member of Tizona, Werewolf, F-Star, Bicara, Apeximmune and T7/Imreg Bio; is a consultant for BMS, Incyte, Regeneron, Ono Pharma and Avidity Partners; and receives research funding from BMS and Novasenta. The other authors declare no competing interests.

Peer review

Peer review information

Nature Immunology thanks Mark Middleton and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Nick Bernard, in collaboration with the Nature Immunology team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aggarwal, V., Workman, C.J. & Vignali, D.A.A. LAG-3 as the third checkpoint inhibitor. Nat Immunol 24, 1415–1422 (2023). https://doi.org/10.1038/s41590-023-01569-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-023-01569-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer