Roles of coinhibitory molecules B7-H3 and B7-H4 in esophageal squamous cell carcinoma

Abstract

The coinhibitory molecules, B7-H3 and B7-H4, have shown negative regulation in T cell activation and tumor-associated macrophage (TAM) polarization in tumor-specific immunity. Here, we investigated the expression of B7-H3 and B7-H4 in human and murine esophageal squamous cell carcinoma (ESCC) tissues to define their clinical significance and mechanism in a tumor microenvironment. In the present study, B7-H3 and B7-H4 were expressed in 90.6 and 92.7 % samples, respectively. High B7-H3 and B7-H4 expression was associated with advanced TNM stage and lymph node metastasis (p < 0.05, respectively). Patients with both B7-H3 and B7-H4 high-expressed tumors had the poorest prognosis (26.7 months), whereas those with both low-expressed tumors had the best survival (56.7 months). B7-H3 and B7-H4 expression were inclined to be positively related to the infiltration intensity of Treg cells and TAMs (p < 0.05, respectively), and B7-H3 expression is negatively associated with the intensity of CD8(+) T cells (p < 0.05). In 4-nitroquinoline 1-oxide (4-NQO)-induced murine models, high B7-H3 expression could only be detected at carcinoma stage, but abnormal B7-H4 expression appeared a little earlier at dysplasia stage. In vitro studies revealed that knockdown of B7-H3 on tumor cells suppressed ESCC cell migration and invasion, while knockdown of B7-H4 could inhibit ESCC cell growth. Overall, B7-H3 and B7-H4 are involved in ESCC progression and development and their coexpression could be valuable prognostic indicators. Interference of these negative regulatory molecules might be a new strategy for treating ESCC.

Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

“…This is further supported by another study in esophageal squamous cell carcinoma where expression of both genes was negatively correlated with the infiltration of CD8+ T-cells [34]. …”

The Role of B7 Family Molecules in Maternal–Fetal Immunity

“…In B7-H3 −/− mice, Th1 differentiation is induced in response to more severe airway inflammation, faster experimental autoimmune encephalomyelitis development and higher autoantibody concentrations. In patients who suffer esophageal squamous cell carcinoma, B7-H3 expression is likely to be positively related to the infiltration intensity of Tregs (82). These studies provide support for the development of new therapies for some pregnancy complications characterized by an impaired immunological status.…”

B7-H3 Overexpression Predicts Poor Survival of Cancer Patients: A Meta-Analysis

“…As members of B7 family, higher B7-H1 expression in human cancer tissues of [51] renal cell carcinoma [52] ovarian cancer [53] non-small cell lung cancer [41], esophageal cancer [54], malignant pleural mesothelioma [55] and colorectal carcinoma [56] is significantly correlated with poor prognosis, while in breast cancer [57], non-small cell lung cancer [58], ovarian cancer [59], renal cell carcinoma [60], pancreatic cancer [26], oral squamous cell carcinoma [61], cholangiocarcinoma [62], hepatocellular carcinoma [63] and esophageal squamous cell carcinoma [64], aberrant expression of B7-H4 has been demonstrated to be associated with a poor clinical outcome. Therefore, we conclude that B7 family members play similar role as negative prognostic factors in tumor development.…”