LAG3’s Enigmatic Mechanism of Action

Graydon, Colin; Mohideen, Shifa; Fowke, Keith R.

doi:10.3389/fimmu.2020.615317

Cited by 121 publications

(111 citation statements)

References 57 publications

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“…LAG-3 binds with major histocompatibility complex class II (MHC II) with a higher affinity than CD4+ [ 27 ]. Moreover, LAG-3 can bind with the LSECtin, a member of the C-type lectin receptor superfamily, typically exposed on tumor cell membranes, and with the fibrinogen like protein 1 (FGL-1), which is part of the fibrinogen protein superfamily [ 28 ]. Several trials have reported that LAG-3 regulates inhibitory effect on T cells synergizing with the PD-1/PD-L1 axis [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of Soluble LAG3 and Soluble Immune Checkpoints Profile in Advanced Head and Neck Cancer: A Pilot Study

Botticelli

Zizzari

Scagnoli

et al. 2021

JPM

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Unresectable recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has a very poor prognosis. Soluble immune checkpoints (sICs) are circulating proteins that result from the alternative splicing of membrane proteins and can modulate the immune response to cancer cells. The aim of our pilot study was to determine the possible role of a comprehensive evaluation of sICs in the classification of prognosis and response to treatment in patients with advanced disease. We evaluated several sICs (CD137, CTLA-4, PD-1, PD-L1, PD-L2, TIM3, LAG3, GITR, HVEM, BTLA, IDO, CD80, CD27, and CD28) from peripheral blood at baseline and investigated the association with clinical characteristics and outcomes. A high baseline soluble LAG3 (sLAG3 > 377 pg/mL) resulted in an association with poor PFS and OS (p = 0.047 and p = 0.003, respectively). Moreover, sLAG3 emerged as an independent prognostic factor using an MVA (p = 0.005). The evaluation of sICs, in particular sLAG3, may be relevant for identifying patients with worse prognoses, or resistance to treatments, and may lead to the development of novel targeted strategies.

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Section: Discussionmentioning

confidence: 99%

The Role of Soluble LAG3 and Soluble Immune Checkpoints Profile in Advanced Head and Neck Cancer: A Pilot Study

Botticelli

Zizzari

Scagnoli

et al. 2021

JPM

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“…LAG-3 is, along with PD-1/PD-L1 and CTLA-4, a promising target in cancer immunotherapy, since it plays a pivotal role in anti-tumor immunity [ 42 ]. LAG-3 blockade, alone or in combination with other ICBs, has demonstrated promising results in clinical trials [ 17 , 19 , 42 , 43 , 44 ]. Yet, little is known about the mechanisms of action underlying LAG-3 blockade in cancer [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…LAG-3 blockade, alone or in combination with other ICBs, has demonstrated promising results in clinical trials [ 17 , 19 , 42 , 43 , 44 ]. Yet, little is known about the mechanisms of action underlying LAG-3 blockade in cancer [ 43 ]. Relatlimab, an anti-LAG-3 blocking mAb, is currently one of the most advanced mAbs in clinical trials targeting solid tumors and hematological malignancies.…”

Section: Discussionmentioning

confidence: 99%

LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia

Sordo‐Bahamonde

Lorenzo‐Herrero

González-Rodríguez

et al. 2021

Cancers

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The inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignancy. LAG-3 is an immune checkpoint receptor that negatively regulates T cell-mediated responses by inducing an hyporesponsive state, thus promoting tumor escape. Patients with chronic lymphocytic leukemia (CLL) develop a profound immune suppression that leads to lessened immunosurveillance and increased risk of developing a secondary neoplasia. In the study herein, we report the profound dysregulation of LAG-3 on leukemic cells in CLL. Likewise, natural killer (NK) and T cells showed increased LAG-3 expression, hence suggesting a role for this checkpoint in CLL-associated immunosuppression. High LAG-3 expression, as well as high levels of soluble LAG-3 (sLAG-3), correlated with adverse cytogenetics and poor outcome in patients with CLL, highlighting the clinical relevance of this immune checkpoint. Treatment of peripheral blood mononuclear cells (PBMCs) from patients with CLL with relatlimab, a new anti-LAG-3 blocking antibody currently evaluated in numerous clinical trials, depleted leukemic cells and restored NK cell- and T cell-mediated responses. Moreover, combination of LAG-3 with the immunomodulatory drug (IMiD) lenalidomide significantly increased IL-2 production by T cells and antibody-dependent cytotoxicity (ADCC) mediated by NK cells. Altogether, these data provide new insights into the potential anti-leukemic effects of relatlimab, currently in clinical trials in CLL, and provides the rationale to further investigate its combination with IMiDs for the management of hematological malignancies.

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“…Lymphocyte activation gene-3 (LAG-3), also known as CD223, is expressed on multiple cell types including conventional T cells, NK cells, B cells [ 109 ], and unconventional T cells [ 109 , 110 , 111 ]. LAG-3 is an IgSF transmembrane protein with four extracellular domains that have similar folding patterns with CD4 in both humans and mice, indicating that LAG-3 can also bind to MHC-II, although at a different site than CD4 [ 112 ].…”

Section: Lag-3mentioning

confidence: 99%

“…LAG-3 is an IgSF transmembrane protein with four extracellular domains that have similar folding patterns with CD4 in both humans and mice, indicating that LAG-3 can also bind to MHC-II, although at a different site than CD4 [ 112 ]. However, the intracellular regions of LAG-3 and CD4 do not have similarities [ 109 , 112 ]. Other LAG-3 ligands include FGL-1 (Fibrinogen-like Protein 1), Gal-3 (Galectin-3), and LSECtin (Lymph Node Sinusoidal Endothelial Cell C-type Lectin) and each has been shown to induce LAG-3-mediated inhibition of T cell activation [ 113 , 114 , 115 ], supporting the idea that LAG-3 could exert its inhibitory action independently of CD4.…”

Section: Lag-3mentioning

confidence: 99%

Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in γδ T, MAIT, and NKT Cells

Tardos

Baglioni

Bekiaris

2021

Cancers

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In recent years, checkpoint inhibitor (CPI) therapy has shown promising clinical responses across a broad range of cancers. However, many patients remain unresponsive and there is need for improvement. CPI therapy relies on antibody-mediated neutralization of immune inhibitory or checkpoint receptors (ICRs) that constitutively suppress leukocytes. In this regard, the clinical outcome of CPI therapy has primarily been attributed to modulating classical MHC-restricted αβ T cell responses, yet, it will inevitably target most lymphoid (and many myeloid) populations. As such, unconventional non-MHC-restricted gamma delta (γδ) T, mucosal associated invariant T (MAIT) and natural killer T (NKT) cells express ICRs at steady-state and after activation and may thus be affected by CPI therapies. To which extent, however, remains unclear. These unconventional T cells are polyfunctional innate-like lymphocytes that play a key role in tumor immune surveillance and have a plethora of protective and pathogenic immune responses. The robust anti-tumor potential of γδ T, MAIT, and NKT cells has been established in a variety of preclinical cancer models and in clinical reports. In contrast, recent studies have documented a pro-tumor effect of innate-like T cell subsets that secrete pro-inflammatory cytokines. Consequently, understanding the mechanisms that regulate such T cells and their response to CPI is critical in designing effective cancer immunotherapies that favor anti-tumor immunity. In this Review, we will discuss the current understanding regarding the role of immune checkpoint regulation in γδ T, MAIT, and NKT cells and its importance in anti-cancer immunity.

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LAG3’s Enigmatic Mechanism of Action

Cited by 121 publications

References 57 publications

The Role of Soluble LAG3 and Soluble Immune Checkpoints Profile in Advanced Head and Neck Cancer: A Pilot Study

The Role of Soluble LAG3 and Soluble Immune Checkpoints Profile in Advanced Head and Neck Cancer: A Pilot Study

LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia

Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in γδ T, MAIT, and NKT Cells

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