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No more LAGging behind PD-1: uncovering the unique role of LAG-3 in T-cell exhaustion

Cellular & Molecular Immunology volume 21, pages 1351–1353 (2024)Cite this article

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Exhausted T (Tex) cells are a distinct subset of T cells that arise in response to prolonged antigen exposure during chronic infections or cancer. Although Tex cells exhibit reduced functionality, they still retain some protective abilities. Exhausted CD8+ T cells are a heterogeneous group consisting of four subsets: progenitor, intermediate, effector, and terminally exhausted. Each subset is characterized by distinct transcriptional, epigenetic, and functional traits [1]. Recent studies have indicated that the progenitor and intermediate Tex subsets are mainly responsible for the proliferative surge observed during anti-PD-1 immunotherapy, which results in the production of a large pool of functional effector cells, thereby sustaining the antitumor immune response [2]. However, blocking the PD-1 pathway alone typically fails to achieve lasting disease control in most patients. Simultaneous blockade of PD-1 and other immune checkpoint receptors can enhance CD8+ T-cell-mediated immunity, leading to more effective treatment outcomes.

Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint receptor that is highly upregulated in exhausted T cells, hindering the development of protective immunity and making it a key target for cancer therapy. Relatlimab, a LAG-3-blocking antibody, was approved by the FDA in 2022 for use in combination with nivolumab, an anti-PD-1 antibody, to treat metastatic melanoma [3, 4]. Although the combination of relatlimab and nivolumab has shown clinical promise, it remains unclear whether this therapy synergistically rejuvenates exhausted T cells and what the underlying mechanisms of action might be.

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References

  1. Zander R, Cui W. Exhausted CD8(+) T cells face a developmental fork in the road. Trends Immunol. 2023;44:276–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dammeijer F, van Gulijk M, Mulder EE, Lukkes M, Klaase L, van den Bosch T, et al. The PD-1/PD-L1-Checkpoint Restrains T-cell Immunity in Tumor-Draining Lymph Nodes. Cancer Cell. 2020;38:685–700.e8.

    Article  CAS  PubMed  Google Scholar 

  3. Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022;386:24–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Long GV, Stephen Hodi F, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, et al. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evid. 2023;2:EVIDoa2200239.

    Article  PubMed  Google Scholar 

  5. Andrews LP, Butler SC, Cui J, Cillo AR, Cardello C, Liu C, et al. LAG-3 and PD-1 synergize on CD8(+) T cells to drive T-cell exhaustion and hinder autocrine IFN-gamma-dependent anti-tumor immunity. Cell. 2024;187:4355–72.e22.

    Article  CAS  PubMed  Google Scholar 

  6. Cillo AR, Cardello C, Shan F, Karapetyan L, Kunning S, Sander C, et al. Blockade of LAG-3 and PD-1 leads to coexpression of cytotoxic and exhaustion gene modules in CD8(+) T cells to promote antitumor immunity. Cell. 2024;187:4373–88.e15.

    Article  CAS  PubMed  Google Scholar 

  7. Ngiow SF, Manne S, Huang YJ, Azar T, Chen Z, Mathew D, et al. LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T-cell NK receptor expression and cytotoxicity. Cell. 2024;187:4336–54.e19.

    Article  CAS  PubMed  Google Scholar 

  8. Guy C, Mitrea DM, Chou PC, Temirov J, Vignali KM, Liu X, et al. LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving coreceptor-Lck dissociation. Nat Immunol. 2022;23:757–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zander R, Schauder D, Xin G, Nguyen C, Wu X, Zajac A, et al. CD4(+) T-Cell Help Is Required for the Formation of a Cytolytic CD8(+) T-Cell Subset that Protects against Chronic Infection and Cancer. Immunity. 2019;51:1028–42.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by an intramural grant from KIST to YP, as well as grants from the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (NRF-2020M3A9G7103935 and RS-2024-00338729 to HJ and RS-2024-00337093 to YP).

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  1. Chemical and Biological Integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, South Korea

    Yunju Jo & Yoon Park

  2. Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea

    Hyung-seung Jin

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  1. Yunju Jo
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Correspondence to Hyung-seung Jin or Yoon Park.

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Jo, Y., Jin, Hs. & Park, Y. No more LAGging behind PD-1: uncovering the unique role of LAG-3 in T-cell exhaustion. Cell Mol Immunol 21, 1351–1353 (2024). https://doi.org/10.1038/s41423-024-01227-w

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