The superfamily member B7/CD28 have previously been shown to serve potential roles in the immune response, and these molecules have been revealed to be effective diagnostic markers and therapeutic targets in cancer (3, 19). The newly discovered member of the B7 family B7-H6 interacted with its receptor on NK cells, namely, NKp30, and played an important role in NK cell-mediated immune responses (11).
NK cells were important immune cells in the body. It was a core cell of the natural immune system and can eliminate tumour cells. NK-cells activation was regulated by some activation receptors or inhibition receptors on the cell surface (10). The major activating receptors included NKG2D and the natural cytotoxicity receptors (NCRs) such as NKp46, NKp30, and NKp44 (20). NKp30 can promote NK cells to recognize and kill tumor cells, either alone or together with other stimulation receptors (21-23). The HLA–B-associated transcript 3 (BAT3) and the pp65 proteins have been shown to bind NKp30, but they don’t correspond to tumour cell surface ligands because pp65 was a human cytomegalovirus tegument protein (24) and BAT3 was a nuclear protein released upon heat shock treatment (25). B7-H6 is a potent ligand for NKp30, and it doesn’t bind any other CD28 family members nor other NCRs (12). B7-H6 expressed on tumour cells contacted NKp30 through the complementarity-determining region (CDR)-like loops of its V-like domain (26). NK cells eliminate B7-H6-expressing tumour cells either directly via cytotoxicity or indirectly by cytokine secretion11. Eva Schlecke et al. illustrated that tumour cells impeded NK-mediated recognition by metalloprotease-mediated shedding of B7-H6 (27). Soluble B7-H6 generated by ectodomain shedding is another form of B7-H6 (11). Soluble B7-H6 was capable to inhibit the binding of anti-NKp30 mAbs to NKp30 and to prevent NKp30-mediated NK cell triggering (27,28). Taken together, these data on B7-H6/ NKp30 interaction provided a theoretical basis for the development of novel cancer treatments.
In recent years, immune checkpoint inhibition with antibodies that block cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have led to meaningful improvements in survival and have brought tumour immunotherapy into a new era (29,30) .Several clinical studies in esophageal cancer using PD-1 inhibitors, such as nivolumab or pembrolizumab, are in progress with recent promising results (31-33). However, the relationship between PD-1/PD-L1 expression in esophageal cancer tissue and prognosis remains controversial. To date, no good biomarker has been found to guide treatment and prognosis. Abnormal B7-H6 expression was found in many human cancer types, suggesting that B7-H6 expressed important clinical significance. The present study provided the first investigation into the relationship between the prognostic and clinical value of B7-H6 expression in ESCC tissue. IHC staining demonstrated that B7-H6 expression was present in most ESCC tissue samples, which was consistent with the findings of other studies (14,17,34). We also found that the expression level of B7-H6 correlated with T stage and lymphatic metastasis status, which demonstrated that B7-H6 expression might be a marker to identify the T stage and lymphatic metastasis status of esophageal squamous cell carcinoma. This result is similar to the findings of studies in gastric carcinoma, ovarian cancer, non-small cell lung cancer, astrocytoma, breast cancer and other cancers (14,15,17,34-36). In addition, Cox regression analysis and the log-rank test revealed that B7-H6 expression level was independent prognostic factor for ESCC. Patients with high B7-H6 expression had significantly worse survival than those with low B7-H6 expression, suggesting that high B7-H6 expression is a predictor of poor prognosis. This result is similar to data from other researchers (15,35,36). Thus, B7-H6 may be regarded as a possible biomarker for predicting the OS of ESCC patients, and also serve as an independent prognostic index .In the past three years, some studies of the knockdown of B7-H6 expression in tumours have been carried out (16,37,38) and indicated that B7-H6 may be a potential therapeutic target in several human cancers. Therefore, it is believed that further studies on the expression of B7-H6 at the gene level and the knockdown of B7-H6 expression may also have certain clinical value in determining the prognosis of ESCC patients.
Still, our study has some limitations. Firstly, its retrospective nature, potential selection bias, and confounding bias, were unavoidable. Secondly, all tumour samples were all from patients of China, which may differ from other ethnics and region. Thirdly, it may be more meaningful to detect the B7-H6 expression in the protein and gene level using western bolt, enzyme-linked immunosorbent assay (ELISA) or gene chip. And further validate the phenotype change via altering the expression of B7-H6 in ESCC is meaningful.