Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

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 LAG...

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Published inFrontiers in immunology Vol. 12; p. 785091
Main Authors Shi, An-Ping, Tang, Xi-Yang, Xiong, Yan-Lu, Zheng, Kai-Fu, Liu, Yu-Jian, Shi, Xian-Gui, Lv, Yao, Jiang, Tao, Ma, Nan, Zhao, Jin-Bo
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 17.01.2022
Subjects
Animals
Antigens, CD - immunology
Antineoplastic Agents, Immunological - immunology
FGL1
Fibrinogen - immunology
Humans
immune checkpoint
immune response
immune therapy
Immunology
LAG3
Ligands
Neoplasms - immunology
tumor
Tumor Microenvironment - immunology
LAG3
immune therapy
immune response
FGL1
tumor
immune checkpoint
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Summary: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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Reviewed by: Rafael Rosell, Catalan Institute of Oncology, Spain; Theresa L. Whiteside, University of Pittsburgh, United States
Edited by: Ignacio Melero, University of Navarra, Spain
These authors have contributed equally to this work and share first authorship
This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2021.785091