Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class I (MHC I) molecule, and under physiological conditions, its expression is strictly restricted to the maternal–fetal interface and immune-privileged organs where HLA-G is expected to contribute to establishment and maintenance of immune tolerance. However, the expression of HLA-G has been found in various types of tumors, and the level of its expression frequently correlates with high-grade histology and poor prognosis, raising the possibility that it may play a negative role in tumor immunity. ILT2 and ILT4, present on a broad of immune cells, have been identified as the main receptors engaging HLA-G, and their interactions have been found to allow the conversion of effectors like NK cells and T cells to anergic or unresponsive state, activated DCs to tolerogenic state, and to drive the differentiation of T cells toward suppressive phenotype. Therefore, tumors can employ HLA-G to modulate the phenotype and function of immune cells, allowing them to escape immune attack. In this review, we discuss the mechanism underlying HLA-G expression and function, its role played in each step of the tumor-immunity cycle, as well as the potential to target it for therapeutic benefit.
Highlights
Human leukocyte antigen-G (HLA-G) is a member of the nonclassical major histocompatibility complex (MHC) class I family
Many immunosuppressive mechanisms are evolved by the host immune system to protect tissue damage caused by excessive or inappropriate immune activation, but they provide opportunities for tumor to evade antitumor immune responses
HLA-G expression is strictly restricted to the maternal–fetal interface and immune-privileged organs where it is expected to contribute to establishment and maintenance of immune tolerance
Summary
Human leukocyte antigen-G (HLA-G) is a member of the nonclassical major histocompatibility complex (MHC) class I family. It was learned that inhibitory receptors, ILT2 and ILT4, were responsible for HLA-G-mediated inhibitory effect on NK cells [2]. Numerous studies reveal that ILT2 and ILT 4 are broadly expressed on a wide range of immune cells, such as NK, T, B cells, and DCs, raising the possibility that HLA-G may exert immunosuppressive function on these cells [3]. A series of studies provided strong experimental support for this idea, namely, the interaction of HLA-G with these inhibitory receptors can inhibit proliferation and cytotoxicity of. HLA-G is reported to bind CD8 and KIR2DL4, resulting in the apoptosis of activated CD8+ T cells and the inhibition of NK-mediated cytotoxicity, respectively [1, 11]. We will discuss how HLA-G expression is regulated under normal or abnormal conditions, and highlight the role of HLA-G played in tumor escape as well as the potential to target it for therapeutic benefit
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