Understanding LAG-3 Signaling

Chocarro, Luisa; Blanco, Ester; Zuazo, Miren; Arasanz, Hugo; Bocanegra, Ana; Fernández-Rubio, Leticia; Morente, Pilar; Fernández-Hinojal, G.; Echaide, Miriam; Garnica, Maider; Ramos, Pablo; Vera, Ruth; Kochan, Grazyna; Escors, David

doi:10.3390/ijms22105282

Cited by 86 publications

(51 citation statements)

References 125 publications

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“…Moreover, patients with high serum levels of LAG-3 showed significantly shorter OS than patients with low levels of LAG-3, and further multivariate analysis confirmed that pre-TACE LAG-3 level was an independent indicator for OS. The similar results have been reported in various types of cancer(38). Although PD-L1 expression was not significantly associated with OS, we still…”

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confidence: 90%

Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients With Transarterial Chemoembolization

et al. 2021

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BackgroundTransarterial chemoembolization (TACE) stands for the most commonly utilized therapy for hepatocellular carcinoma (HCC) worldwide. This study was to explore the potential predictive and prognostic roles of LAG-3 and PD-L1 as serum biomarkers in HCC patients underwent TACE treatment.MethodsA total of 100 HCC patients receiving TACE as well as 30 healthy controls were enrolled in the study. Serum LAG-3 and PD-L1 levels were determined at baseline and 3 day after TACE using enzyme-linked immunosorbent assay (ELISA).ResultsWe found serum levels of LAG-3 and PD-L1 were significantly elevated in HCC patients compared with healthy controls. Interestingly, patients with low pre-TACE and post-TACE levels of LAG-3 but not PD-L1 had a high probability of achieving an objective response (OR) after TACE treatment. Additionally, high pre-TACE LAG-3 level was correlated with poor disease outcome, and the patients with both high serum LAG-3 and PD-L1 level had the shorter overall survival (OS) than patients who are either PD-L1 or LAG-3 high or both PD-L1 and LAG-3 low. High pre-TACE serum LAG-3 level was positively associated with more cirrhosis pattern, advanced BCLC stage, pre-TACE alanine aminotransferase (ALT) level, and pre-TACE aspartate aminotransferase (AST) level. Furthermore, in 50 patients who underwent TACE, the serum LAG-3 level was significantly decreased at 3 day after TACE.ConclusionBoth pre-TACE and post-TACE serum LAG-3 levels could serve as powerful predictors for tumor response of TACE, and high pre-TACE serum LAG-3 level was an indicator for poor prognosis in HCC.

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confidence: 90%

Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients With Transarterial Chemoembolization

et al. 2021

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“…The regulation of LAG3 is tightly associated with the production of cytokines, especially immune-related cytokines. LAG3 can stimulate the production of mature DC-derived IL-12 and TNF-α ( 54 ). In melanoma, the methylation of LAG3 promoter regions may inhibit the mRNA expression of IFN-γ-and IFN-γ-regulated genes, including STAT1/2, JAK2, and IRF9 ( 35 ).…”

Section: The Biological Effect Of Lag3/fgl1 On Different Tumorsmentioning

confidence: 99%

Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

et al. 2022

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LAG3 is the most promising immune checkpoint next to PD-1 and CTLA-4. High LAG3 and FGL1 expression boosts tumor growth by inhibiting the immune microenvironment. This review comprises four sections presenting the structure/expression, interaction, biological effects, and clinical application of LAG3/FGL1. D1 and D2 of LAG3 and FD of FGL1 are the LAG3-FGL1 interaction domains. LAG3 accumulates on the surface of lymphocytes in various tumors, but is also found in the cytoplasm in non-small cell lung cancer (NSCLC) cells. FGL1 is found in the cytoplasm in NSCLC cells and on the surface of breast cancer cells. The LAG3-FGL1 interaction mechanism remains unclear, and the intracellular signals require elucidation. LAG3/FGL1 activity is associated with immune cell infiltration, proliferation, and secretion. Cytokine production is enhanced when LAG3/FGL1 are co-expressed with PD-1. IMP321 and relatlimab are promising monoclonal antibodies targeting LAG3 in melanoma. The clinical use of anti-FGL1 antibodies has not been reported. Finally, high FGL1 and LAG3 expression induces EGFR-TKI and gefitinib resistance, and anti-PD-1 therapy resistance, respectively. We present a comprehensive overview of the role of LAG3/FGL1 in cancer, suggesting novel anti-tumor therapy strategies.

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“…Therefore, there is an unmet need for additional interventions that can promote response to or reverse resistance to therapy with immune checkpoint blocking mAbs that target CTLA-4, PD-1 or PD-L1. Since LAG-3 is often co-expressed with PD-1 on tumor-infiltrating lymphocytes [ 42 , 43 ], it has been proposed that blockade of LAG-3 in conjunction with blockade of PD-1 could be promising to increase treatment response [ 26 , 44 ]. Preclinical studies [ 37 ] and the preliminary results of the RELATIVITY-047 trial [ 28 – 30 ] confirm this hypothesis and suggest that stratification of patients based on LAG-3 expression allows predicting therapy outcome.…”

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confidence: 99%

Evaluation of single domain antibodies as nuclear tracers for imaging of the immune checkpoint receptor human lymphocyte activation gene-3 in cancer

et al. 2021

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Recent advancements in the field of immune-oncology have led to a significant increase in life expectancy of patients with diverse forms of cancer, such as hematologic malignancies, melanoma and lung cancer. Unfortunately, these encouraging results are not observed in the majority of patients, who remain unresponsive and/or encounter adverse events. Currently, researchers are collecting more insight into the cellular and molecular mechanisms that underlie these variable responses. As an example, the human lymphocyte activation gene-3 (huLAG-3), an inhibitory immune checkpoint receptor, is increasingly studied as a therapeutic target in immune-oncology. Noninvasive molecular imaging of the immune checkpoint programmed death protein-1 (PD-1) or its ligand PD-L1 has shown its value as a strategy to guide and monitor PD-1/PD-L1-targeted immune checkpoint therapy. Yet, radiotracers that allow dynamic, whole body imaging of huLAG-3 expression are not yet described. We here developed single-domain antibodies (sdAbs) that bind huLAG-3 and showed that these sdAbs can image huLAG-3 in tumors, therefore representing promising tools for further development into clinically applicable radiotracers.

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Understanding LAG-3 Signaling

Cited by 86 publications

References 125 publications

Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients With Transarterial Chemoembolization

Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients With Transarterial Chemoembolization

Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

Evaluation of single domain antibodies as nuclear tracers for imaging of the immune checkpoint receptor human lymphocyte activation gene-3 in cancer

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