Objective: B7-H3 is a member of the B7 family of immune checkpoint molecule. Although B7-H3 has been shown to regulate T cell-mediated peripheral immune response, whether it also correlated with NK cell exhaustion in ovarian cancer remains unclear. The purpose of this study was to explore the mechanism of B7-H3 regulating NK-cell proliferation and function.
Material and methods: To investigate the relationship between B7-H3 expression and the NK-cell function in ovarian cancer, human ovarian tumor tissues and cell lines were first examined the protein and mRNA expression of B7-H3 by quantitative real-time PCR (qRT-PCR), Immunohistochemistry and Western-blot assays. Then we established B7-H3 knockout cell lines and measured the cytotoxicity of NK cells on these cells by LDH release assay and Flow Cytometry. In addition, we analyzed B7-H3 in the regulation of glycolysis and glycolysis-related proteins by Glycolysis Stress Test, Glucose Consumption Assay and Western-blot. Moreover, luciferase reporter assay was used to confirm the directly regulation of miR-29c to B7-H3. Finally, we carried out in vivo experiments.
Results: We observed that tumor-expressed B7-H3 inhibits NK-cell function in vitro and in vivo, and is associated with glycolysis of ovarian cancer cell. Therapeutically, B7-H3 blockade prolonged the survival of SKOV3 tumor-bearing mice. In addition, miR-29c improved the anti-tumor efficacy of NK-cell by directly targeting B7-H3 in vitro were observed, but not in vivo.
Conclusion: Our results demonstrate that miR-29c downregulates B7-H3 to inhibit NK-cell exhaustion and associated with glycolysis, which suggest that NK cells may be a new target of anti-B7-H3 therapy in ovarian cancer patients.
Keywords: B7-H3; NK cells; Ovarian cancer; miR-29c.
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