LAG-3 and MHC II Pathway

Introduction

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.

Preclinical and Clinical Development of Drugs for LAG-3 and MHC II Pathway

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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