LAG-3 is a surface molecule located closely to CD4 but sharing less than 20% homology at the amino acid level. The homology to CD4 suggests that LAG-3 binds to major histocompatibility complex-II (MHC-II) on antigen-presenting cells (APCs) with stronger affinity. LAG-3 preferentially suppresses the activation of T cells and, presumably, other LAG-3 expressing cells, including CD8+ T cells, by binding to MHC class II proteins. The inhibitory function of LAG-3 is independent of CD4 competition but rather dependent on its cytoplasmic domain to deliver inhibitory signaling.
The LAG-3/MHC-II interaction may also act as bidirectional inhibitory signaling shared by immune cells and tumor cells. LAG-3-expressing Tregs may utilize this mechanism to enforce tolerance by indirectly inhibiting DC function. Until now, knowledge of the exact signal transduction mechanism of LAG-3 is still limited. However, ample evidence has indicated that LAG-3 signaling plays a negative regulatory role in T helper 1 (Th1) cell activation, proliferation, and cytokine secretion. During tumorigenesis and cancer progression, tumor cells can exploit this pathway to escape from immune surveillance.
Fig.1 The binding of LAG-3 and MHC class II. (Lui, 2018)
Cancer immunotherapy and tumor microenvironment have been at the forefront of cancer research over the past several decades. Waves of immune checkpoint therapy especially targeting PD-1/PD-L1 have led to remarkable success in treating advanced malignancies. There is now great interest in the LAG-3 and MHC II pathway, which forms part of the second wave of immune checkpoint targets because LAG-3 is expressed alongside the immunoregulatory receptor PD-1 on tumor-infiltrating lymphocytes and is associated with T cell exhaustion.
Many preclinical studies confirmed that the blockade of LAG-3 could support anti-cancer immune responses, leading to a significant delay in tumor growth. More recent clinical research shows that LAG-3 therapy is more effective when combined with other anti-cancer treatments. For example, LAG-3 blockade combined with tumor-associated antigen vaccination can increase the number of tumor-infiltrating, activated CD8+ T cells. Moreover, co-blockade or genetic deletion of LAG-3 and PD-1 has shown strong therapeutic effects in various mouse tumor models.
As checkpoint immunotherapies targeting inhibitory coreceptors revolutionized cancer treatment, LAG-3 is expected to be a highly promising therapeutic target in cancer immunotherapy. Currently, at least ten kinds of LAG-3 blockade agents have been evaluated in preclinical or clinical settings and purposed to treat cancer.
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