Abstract
Phenotypic heterogeneity has been observed in most malignancies, which represents a considerable challenge for tumor therapy. In recent decades, the biological function and clinical significance of the human leukocyte antigen (HLA)-G have been intensively explored. It is now widely accepted that HLA-G is a critical marker of immunotolerance in cancer cell immune evasion and is strongly associated with disease progress and prognosis for cancer patients. Moreover, it has recently been emphasized that the signaling pathway linking HLA-G and immunoglobulin-like transcripts (ILTs) is considered an immune checkpoint. In addition, HLA-G itself can generate at least seven distinct isoforms, and intertumor and intratumor heterogeneity of HLA-G expression is common across different tumor types. Furthermore, HLA-G heterogeneity in cancers has been related to disease stage and outcomes, metastatic status and response to different therapies. This review focuses on the heterogeneity of HLA-G expression in malignant lesions, and clinical implications of this heterogeneity that might be relevant to personalized treatments are also discussed.
Highlights
Cancer is a very complex and heterogeneous disease that involves a broad range of mixed cells with distinct features
The mechanisms involved in human leukocyte antigen (HLA)-G/receptor ( immunoglobulin-like transcript 2 (ILT2) and ILT4) mediated immune suppression have been documented in previous studies and include impairment of immune cell proliferation, differentiation, cytotoxicity, cytokine secretion and chemotaxis; and induction of regulatory cells and myeloid derived suppressive cells (MDSCs) or M2 type macrophages [31,32,33] (Figure 2)
Tumor heterogeneity can be caused by genetic mutations during clonal evolution, and/or by tumor microenvironment selective pressure during tumor development [143]
Summary
Cancer is a very complex and heterogeneous disease that involves a broad range of mixed cells with distinct features. In the context of heterogeneity of HLA-G expression in cancers, the degree of HLA-G expression and the isoform profiles vary dramatically among tumor types and patients, within tumors of the same type, and between the primary tumor and metastases [10].
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