Abstract
Human leukocyte antigen G (HLA-G) mediates maternal-fetal immune tolerance. It is also considered an immune checkpoint in cancer since it may mediate immune evasion and thus promote tumor growth. HLA-G is, therefore, a potential target for immunotherapy. However, existing monoclonal antibodies directed against HLA-G lack sufficient specificity and are not suitable for immune checkpoint inhibition in a clinical setting. For this reason, it is essential that alternative approaches are explored to block the interaction between HLA-G and its receptors. In this review, we discuss the structure and peptide presentation of HLA-G, and its interaction with the receptors Ig-like transcript (ILT) 2, ILT4, and Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4). Based on our findings, we propose three alternative strategies to block the interaction between HLA-G and its receptors in cancer immunotherapy: (1) prevention of HLA-G dimerization, (2) targeting the peptide-binding groove of HLA-G, and (3) targeting the HLA-G receptors. These strategies should be an important focus of future studies that aim to develop immune checkpoint inhibitors to block the interaction between HLA-G and its receptors for the treatment of cancer.
Highlights
Human leukocyte antigen G (HLA-G) is mainly expressed on the extravillous cytotrophoblasts in the placenta, where it mediates maternal-fetal immune tolerance during pregnancy [1]
Peptides are loaded onto HLA-G in the endoplasmic reticulum (ER) by the peptide loading complex (PLC) formed by the transporter associated with antigen processing (TAP), HLA-G, the oxidoreductase ERp57, and the chaperones tapasin and calreticulin [43,44]
Co-expression of HLA-G and its receptors has been observed in different cancer types, leading to proliferation, migration and invasion of tumor cells upon interaction
Summary
Human leukocyte antigen G (HLA-G) is mainly expressed on the extravillous cytotrophoblasts in the placenta, where it mediates maternal-fetal immune tolerance during pregnancy [1]. The first immune checkpoint inhibitors that were approved by the US Food and Drug Administration (FDA) blocked the interaction between programmed cell death protein 1 (PD-1) and its ligand (PD-1L), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and its ligands CD80 and CD86 [9,10,11] This has led to remarkable therapeutic success in the treatment of multiple cancer types [9,10,11]. The existing monoclonal antibodies directed against HLA-G are not suitable for immune checkpoint inhibition in a clinical setting [17,18,20,21] For this reason, it is essential that alternative approaches are explored to block the interaction between HLA-G and its receptors. Research gaps and future directions for HLA-G-based cancer immunotherapy are discussed and proposed
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