May 21, 2022

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Research progress of tumor immunotherapy targeting LAG-3

Research progress of tumor immunotherapy targeting LAG-3



 

Research progress of tumor immunotherapy targeting LAG-3

 

Foreword

Over the past decade, the discovery of T-cell immune checkpoints ( ICPs ) and the development of CTLA-4 and PD-1/PD-L1 monoclonal antibody inhibitors have revolutionized the field of immuno-oncology.

However, due to tumor resistance, lack of tumor-infiltrating lymphocytes ( TILs ), and the presence of suppressive myeloid cells, only 10-30% of patients show long-term, durable responses, and the frequency of these widely used ICIs is suboptimal .

In addition, the occurrence of immune-related adverse events ( IRAEs ) and acquired drug resistance are huge obstacles.

Therefore, finding new other immune checkpoints related to the tumor microenvironment is called one of the directions to solve these problems.

 

Currently, the list of inhibitory ICPs that negatively regulate antitumor immune responses is growing. Among these new generation ICPs, lymphocyte activation gene-3 ( LAG-3 ) has emerged as one of the most promising and potential targets in cancer therapy.

In the current clinical evaluation, there are as many as 22 blocking monoclonal and double-antibodies against LAG-3.

According to the current clinical results, it is certain that LAG-3 and PD-1 show a significant synergistic effect in promoting immune escape of cancer cells.

Due to the complementarity of LAG3 and PD-1 in mechanism, LAG3 combined with PD-1 has become an important tumor immunotherapy strategy.

 

 

Molecular properties of LAG-3

LAG-3 is a type I transmembrane protein with four Ig-like domains ( D1-D4 ). D1 of LAG-3 consists of 9 β-strands called A, B, C, C’, C”, D, E, F and G chains.

Additional sequences of approximately 30 amino acids are located at C and C’ Between the chains, a loop is formed, called the “extra loop”.

Despite the low sequence similarity, this loop can be observed in both human and mouse LAG-3, and this loop has been reported to be involved in LAG-3 and major Association between histocompatibility complex class II ( MHCII ). In addition, LAG-3 is highly glycosylated with multiple N-glycosylation sites in D2-D4.

Galectin-3 and hepatic sinusoidal endothelial cells Lectin ( LSECtin ) is thought to interact with LAG-3 glycans.

 

The presence of a longer amino acid sequence between D4 and the transmembrane region of LAG-3 is called the “linker peptide”.

Based on a mouse model, metalloproteases ADAM10 and ADAM17 were found to cleave LAG-3 at the CP and release the extracellular domain of LAG-3 in a soluble form.

Therefore, ADAM10 and ADAM17 may regulate the inhibitory effect of LAG-3 by regulating the amount of LAG-3 on the cell surface.

The amino acid sequence homology of human and mouse CP is low, so whether human LAG-3 can also be cleaved by these metalloproteases remains to be further investigated.

 

Research progress of tumor immunotherapy targeting LAG-3

 

The intracellular domain of LAG-3 consists of approximately 60 amino acid residues and lacks typical inhibitory motifs, such as immunoreceptor tyrosine-based inhibitory motifs.

However, it contains several amino acid sequences that are well conserved among different LAG-3 species and are not shared with other inhibitory co-receptors.

These sequences include FSAL in the juxtaposed membrane region, KIEELE in the mid region, 10-15 glutamate tandem repeats, and proline ( EX-repeat ) in the C-terminal region with a tendency but not limitation.

Inhibition of T-cell activation by LAG-3 requires signaling in the intracellular domain, and it can transmit different inhibitory signals through these sequences.

 

 

Expression and ligands of LAG-3

Like PD-1 and CTLA-4, LAG-3 is not expressed on naive T cells, but can be induced on CD4+ and CD8+ T cells upon antigenic stimulation.

LAG-3 is also expressed in CD4+ T cell subsets with suppressive function. Foxp3+ regulatory T ( Treg ) cells constitutively express LAG-3.

 

LAG-3 is also expressed on CD3+CD4-CD8-T cells, TCRαβCD8αα intraepithelial lymphocytes, γδ T cells and NKT cells, and its expression on activated NK cells has been reported to be involved in the killing of MCI-negative target cells in mice effect.

Plasmacytoid dendritic cells and activated B cells also express LAG-3 on their cell surfaces.

However, the functional role of LAG-3 in these cells remains poorly understood. In addition, LAG-3 has also been reported to be expressed on neurons and act as a receptor for α-synuclein fibers.

 

LAG-3 distinguishes the conformation of pMHCII and selectively binds to stable pMHCII. In addition to stable pMHCII, several other molecules have been reported as possible ligands for LAG-3. Galectin-3 and LSECtin have been shown to interact with glycans on LAG-3.

Galectin-3 belongs to the Galectin family and is a soluble galectin-binding lectin secreted by various tumor cells and tumor stromal cells.

LSECtin is a member of the C-type lectin family and is mainly expressed in the liver.

 

Research progress of tumor immunotherapy targeting LAG-3

 

In addition to its immunosuppressive effects, LAG-3 appears to have a distinct role in the nervous system. Mao et al. reported that LAG-3 can bind to α-synuclein fibers, which is implicated in the pathogenesis of Parkinson’s disease. Binding of α-synuclein fibers to LAG-3 triggers endocytosis, cell-to-cell transmission, and neurotoxicity of α-synuclein fibers.

 

 

LAG-3 immunosuppressive effect

LAG-3 expression levels and LAG-3+ cell infiltration in tumors have been consistently associated with tumor progression, poor prognosis, and various types of human tumors .

These results strongly suggest that LAG-3 is involved in a PD-1-like tumor immune escape mechanism.

 

However, the exact signaling pathway of LAG-3 remains unknown. It has been shown that the inhibitory effect of LAG-3 is not caused by the competitive binding of pMHC II with CD4.

It has been reported that LAG-3 may induce an inhibitory mechanism through the FXXL motif present in the proximal region of the membrane and the EX-repeat at the C-terminus.

The inhibitory effect of LAG-3 was abolished upon knockout of the EX repeats or induction of mutations in the FXXL sequence. How LAG-3 interacts with intracellular signaling proteins remains largely unknown.

 

Research progress of tumor immunotherapy targeting LAG-3

 

Studies have shown that LAG-3 can transmit inhibitory signals on activated CD8+ T cells.

Furthermore, Tregs in the TME impair tumor-specific immune responses by downregulating inflammatory cytokines and upregulating inhibitory activity, and LAG-3 has been shown to be critical in supporting Treg activity.

A study of non-small cell lung cancer ( NSCLC ) patients showed that Tregs in tumors express elevated LAG-3 compared to Tregs in peripheral blood and normal tissues.

 

In addition, the expression of LAG-3 on the surface of dendritic cells increases the secretion of immunosuppressive cytokines, such as IL-10 and TGF-β. These cytokines exert inhibitory effects on the activity of CD8+ T cells, NK cells and DCs.

In addition, Tregs directly inhibit pDCs through the LAG-3–pMHC II interaction. These all initiate inhibitory pathways that hinder DC proliferation and maturation.

 

The direct role of LAG-3 expression on activated NK cells is not fully understood. However, LAG-3 has been shown to downregulate proliferation on NKT cells expressing both NK receptors and T cell receptors.

The expression of LAG-3 on B cells has been shown to be T cell-dependent, exerting immunosuppressive activity through the production of IL-10.

In addition, LAG-3 is also expressed in TAMs, and although the role is not fully understood, it can be speculated that LAG-3 expression on TAMs contributes to their tumor-promoting function.

 

 

Clinical Development of LAG-3

Based on preclinical observations, especially benefit in combination with drugs targeting PD-1. So far, at least 20 drugs targeting LAG-3 have been developed.

Includes anti-LAG-3 blocking antibodies ( relatlimab (BMS-986016), Sym022, TSR-033, REGN3767, LAG525, INCAGN2385-101, MK-4280 and BI754111 ) and antagonist bispecific antibodies ( MGD013 (anti-PD-1) /LAG-3), FS118 (Anti-LAG-3/PD-L1) and XmAb22841 (anti-CTLA-4/LAG-3) ) , etc.

 

Research progress of tumor immunotherapy targeting LAG-3

 

Other LAG-3-targeting drugs are also used in cancer treatment. IMP321 is a soluble recombinant fusion protein composed of the extracellular region of LAG-3 and the Fc region of IgG, which activates antigen-presenting cells through MHCII-mediated reverse signaling, resulting in an increase in IL-12 and TNF, CD80 and CD86 raised.

In current clinical trials,The efficacy of IMP321 monotherapy or in combination with other therapies is moderate. The details of reverse signaling through MHCII remain unknown and require careful study.

 

Research progress of tumor immunotherapy targeting LAG-3

 

Anti-LAG-3 depleting antibody ( GSK2831781 ) and agonist antibody ( IMP761 ) have also been reported as potential therapeutics for the treatment of autoimmune diseases.

Although these antibodies are designed to clear or suppress pathogenic T cells, they may also deplete or suppress Treg cells.

Further research to clarify the function of this antibody and the biological properties of LAG-3 is expected to facilitate its development.

 

 


Summary

Checkpoint immunotherapy targeting inhibitory co-receptors PD-1 and CTLA-4 has revolutionized cancer treatment, and LAG-3, as a new generation of discovered inhibitory checkpoint , is expected to be a promising target in cancer therapy point. However, our understanding of LAG-3 is still very limited, and many fundamental questions remain unanswered.

The signal transduction mechanism of LAG-3 is unclear, and its ligands are complex.

LAG-3 is expressed in a variety of cells, however, the function of LAG-3 and the role of LAG-3 blockers in each type of cell have not been elucidated.

We also need to study functional differences, redundancy and synergy between LAG-3 and other co-receptors.

By elucidating the functional properties of LAG-3 in more detail, we can rationally design LAG-3-targeted therapy for various diseases, such as cancer and autoimmune diseases.

 

 

references:

1. LAG-3: from molecular functions to clinical applications. J Immunother Cancer . 2020 Sep;8(2):e001014.

2. The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potentialin Oncology: Third Time’s a Charm. Int J Mol Sci. 2021 Jan; 22(1): 75.

Research progress of tumor immunotherapy targeting LAG-3

(source:internet, reference only)


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