Molecular Pathways: Human Leukocyte Antigen G (HLA-G)

Abstract

Human leukocyte antigen G (HLA-G) is a nonclassical MHC class I molecule that exerts important tolerogenic functions. Its main physiologic expression occurs in the placenta, where it participates in the maternal tolerance toward the fetus. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. It is expressed in various types of primary solid (melanoma, head and neck, lung, urogenital, gastrointestinal, and breast cancers) and hematologic malignancies (acute leukemia, lymphomas) and metastases. HLA-G ectopic expression is observed in cancer, suggesting that its expression is one strategy used by tumor cells to escape immune surveillance. In this review, we will focus on HLA-G expression in cancers and its association with the prognosis. We will highlight the underlying molecular mechanisms of impaired HLA-G expression, the immune tolerant function of HLA-G in tumors, and the potential diagnostic use of membrane-bound and soluble HLA-G as a biomarker to identify tumors and to monitor disease stage. As HLA-G is a potent immunoinhibitory molecule, its blockade remains an attractive therapeutic strategy against cancer.

BRAFV600E in Papillary Thyroid Carcinoma Is Associated with Increased Programmed Death Ligand 1 Expression and Suppressive Immune Cell Infiltration

“…HLA-G is a nonclassic and inhibitory MHC class I molecule expressed at immuno-privileged sites and by the placenta to induce maternal/fetal tolerance that is known to inhibit antigen-presenting, natural killer, and T cells (33,34). Aberrant expression of HLA-G is a known mechanism of tumor-mediated immune tolerance and data suggest that HLA-G expression correlates with tumor growth and poorer prognosis (35,36).…”

Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy

“…In physiological conditions, HLA-G expression was also found in erythroid precursors, cornea, thymic medulla and pancreatic islets (8,(9)(10)(11). However, HLA-G can be neoexpressed in pathological conditions including cancers, transplantation, and inflammatory and autoimmune diseases and viral infections (3,5,12,13).…”

“…With the selection pressure exerted by immune system, various strategies have been developed and applied by tumor cells to avoid recognition and destruction by different immune effectors (1,2). One of the common strategies used by tumor cells to escape innate and adaptive immune response is associated with an induced aberrant expression of the nonclassical class I molecule human leukocyte antigen-G (HLA-G) (3).…”

The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion

“…This might be because cutaneous mastocytosis is too indolent for significant differences in clinical parameters to be detected (40). Structurally, KIR2DL4 is an inhibitory receptor (1, 2); therefore, our finding that KIR2DL4 suppresses KIT-mediated (46,47). Our current data provide another explanation for these reports; that is, mast cells are involved in the HLA-G-KIR2DL4 axis and are able to enhance the invasive property of cancer cells.…”