Human Leukocyte antigen-G (HLA-G) and gastrointestinal malignancy

Malignant conditions can affect any part of the gastrointestinal (GI) tract, including the esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus (1). Currently, conventional TNM staging is the most important prognostic factor for determining the clinical outcome of GI cancer. However, clinical studies have shown that patients with similar stages of the disease may have various outcomes and tend to have clear discrepancy in survival rates (2-5). Because tumor detection and treatment at an early stage can significantly improve patient survival, there has been great interest to find new molecular prognostic markers that can help identify patients at a higher risk of death (6). Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility complex (MHC) class Ib antigen that expresses as seven isoforms, including four membrane-bound (HLA-G1 to HLA-G4) and three soluble (HLA-G5 to HLA-G7) forms (7). It has been demonstrated that HLA-G plays important role in immune tolerance during pregnancy (8). In recent years, there has been strong evidence shown to suggest that the presence of intratumor tumor-infiltrating lymphocytes (TILs) reflects an immune response between tumor cells and immune effector cells. Several studies have shown that the presence of TILs is a prognostic factor for predicting patient survival in various types of cancer (9-13). A consequence of immune-mediated selective elimination of tumor cells is a changing of the tumor phenotype during tumor development, which has recently been referred to as 'cancer immunoediting' (14). Cancer immunoediting is a process that includes three essential phases: elimination, equilibrium, and escape. HLA-G has been postulated to play a role especially in the escape phase of cancer immunoediting (14). The aberrant expression of HLA-G by tumor cells has been suggested to be part of the strategy to escape from the host's immunosurveillance by suppressing tumor reactive CD4+ T-cell proliferation and inhibiting NK-cell-mediated and T-cell-mediated cytolysis (3, 7, 11-13). In non-pathological situations HLA-G expression is largely restricted to extra-villous cytotrophoblastic cells, placental chorionic endothelium, activated monocytes, thymic epithelial cells, nail matrix, cornea, and erythropoietic lineage cells from the bone marrow, and is not found in other healthy tissues expressing MHC class Ia antigens (15). In 1998, Paul et al. described, for the first time the expression of HLA-G in solid tumors (16), and the number of papers published on HLA-G in cancer has increased in recent years such as for melanoma, renal cell carcinoma, carcinoma of the lung, breast carcinoma, …