The Immunoregulatory Protein B7-H3 Regulates Reprogramming Of Cancer Cell Glucose Metabolism Through Reactive Oxygen Species Mediated Stabilization Of Hif-1 Alpha

With the recent success of immunotherapy targeting immune checkpoints, interest in understanding the function of immune checkpoint modulators such as the B7 family proteins escalated. B7-H3 is a transmembrane glycoprotein and a member of the B7 family of immunoregulatory proteins. Extensive studies have shown that B7-H3 is important in regulating the activity of immune cells. We are among the first groups to show that in addition to immunoregulatory function, B7-H3 also has non-immunological functions, which may contribute to its role in tumor progression. Overexpression of B7-H3 is associated with tumor progression and poor patient outcome in multiple types of cancers. However, studies on how B7-H3 regulates cancer growth and metastasis are rare and the mechanisms underlying the role of B7-H3 in cancer malignancy are almost unknown. We and others have shown that B7-H3 mediates breast cancer invasion, metastasis and drug resistance and that silencing B7-H3 delays tumor growth and sensitizes cancer cells to chemotherapeutic agents in immune-independent in vitro and in vivo assays, indicating immunoregulatory B7-H3 also has immune-independent function. In this study, we investigated the role of B7-H3 in cancer cell metabolic reprograming in vitro and in two independent xenograft mouse models. We found that B7-H3 increased glucose uptake and lactate production while it suppressed oxygen consumption in B7-H3 high-expressing cells, indicating that B7-H3 promotes Warburg effect. B7-H3 increased the protein levels of HIF-1α and its downstream targets LDHA and PDK1, which are key enzymes in glycolytic metabolism. Moreover, B7-H3 promotes HIF-1α stability via enhanced reactive oxygen species (ROS) by suppressing the activity of transcription factor Nrf2 and mitochondrial Nrf2 target genes, including antioxidant enzymes SOD1, SOD2 and PRX3. B7-H3 mediated HIF-1α stability is suppressed by ROS scavenger treatment including N-acetylcysteine and PEG-catalase. Metabolic imaging of human breast cancer xenograft in mice further demonstrated that B7-H3 enhances tumor glucose uptake and tumor growth. Together, our results show that B7-H3 regulates cancer glucose metabolism via ROS mediated-HIF1α pathway. By exploring novel functions of B7-H3, our study fills a large knowledge gap in understanding the mechanisms underlying the role of B7-H3 in tumorigenesis and cancer progression, especially in understanding the underappreciated contribution of its non-immunological functions in B7-H3 mediated cancer pathology. The knowledge gained through carrying out the project will be paradigm shifting for B7-H3 biology and will be essential for developing efficient B7-H3 targeted therapy. Citation Format: Sangbin Lim, Hao Liu, Luciana Barnes, Ming Tan. The immunoregulatory protein B7-H3 regulates reprogramming of cancer cell glucose metabolism through reactive oxygen species mediated stabilization of HIF-1α. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 48.