Abstract
Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.
Highlights
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These results suggested that Lag-3 expression was likely epigenetically regulated via methylation [70]
NSCLC patients who do not respond to immunotherapy present highly dysfunctional systemic T lymphocytes that simultaneously express Parkinson’s disease (PD)-1 and Lymphocyte activation gene 3 (LAG-3) following TCR stimulation. These dysfunctional T lymphocytes are resistant to anti-PD-L1/PD-1 monotherapies, possibly due to the expression of LAG3 [42]. It has been shown in different experimental models that LAG-3 and PD-1 are co-expressed in TILs from progressing tumors, and that their co-blockade has synergistic effects against immune escape, increased antitumor response, enhanced T cell proliferation, and cytokine production [41,42,56,93,94]
Summary
MHC-II molecules are considered the canonical ligand of LAG-3, with which it stably interacts through the D1 domain with a significantly higher affinity than with CD4 [20] This association negatively regulates T cell activation, cytotoxicity, and cytokine production [28]. Gal-3 shapes antitumor-specific immune responses by suppressing activated antigen-committed CD8 T cells via LAG-3 expression in the tumor microenvironment and inhibiting expansion of plasmacytoid dendritic cells [35]. This mutant LAG-3 could still inhibit T cells, demonstrating that FGL1/LAG3 interactions correspond to a tumor immune evasion mechanism which is non-redundant to MHC-II binding Taken together, these data suggest that LAG-3 interactions with several ligands are important for its inhibitory function, and unlike what was thought before, LAG-3 does not function primarily by disrupting CD4:MHC-II interactions. LAG-3 has been shown to be expressed in neurons, where it binds to and co-endocytoses with pathologic α-synuclein [59,60,61]
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