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Abstract B31: Tumor-intrinsic B7-H3 regulates drug resistance, metabolism, and pathogenesis in ovarian cancer

B7-H3 (CD276) is a cell surface glycoprotein of B7 family of checkpoint blockade proteins that has been considered a valuable novel biomarker and a promising target for cancer treatment. B7-H3 is overexpressed in a wide variety of human cancers and is associated with tumor progression, metastasis, a...

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Published in:Clinical cancer research 2018-08, Vol.24 (15_Supplement), p.B31-B31
Main Authors: Taylor, Holly, Slamecka, Jaroslav, Musiyenko, Alla, Gavin, Elaine, Norton, Tiffany S., Aragon, Ileana, Young, Taylor, Scalici, Jennifer, Rocconi, Rodney P., Tan, Ming, Silva, Luciana Madeira da
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Language:English
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Summary:B7-H3 (CD276) is a cell surface glycoprotein of B7 family of checkpoint blockade proteins that has been considered a valuable novel biomarker and a promising target for cancer treatment. B7-H3 is overexpressed in a wide variety of human cancers and is associated with tumor progression, metastasis, and poor patient outcome. In addition to its function in cancer immunity, B7-H3 also has tumor-intrinsic functions related to drug resistance, metabolic reprogramming, migration, and invasion of cancer cells. B7-H3 overexpression in the ovarian tumors and tumor vasculature has been reported and B7-H3 monoclonal antibodies have shown inhibitory effects in ovarian cancer xenograft studies. Nonetheless, the molecular pathways regulated by B7-H3 in ovarian cancer remain largely unknown. Here we explored the role of tumor intrinsic B7-H3 in ovarian cancer cells by genetic modulation of B7-H3 expression levels in ovarian cancer cells, using CRISPR/Cas9-mediated B7-H3 knockout and B7-H3 overexpression using retrovirus system for cell transduction. Knockout of B7-H3 in OV-90 cells, which showed high endogenous expression of B7-H3, resulted in decreased glycolysis and oxidative phosphorylation through downregulation of HIF1α, and its downstream target glycolytic proteins LDHA and PDK1. Furthermore, OV-90 B7-H3 KO cells showed decreased phosphorylation of the prosurvival protein STAT3, reduced clonogenic and migratory capability, and increased sensitivity to chemotherapeutic agent carboplatin. Overexpression of B7-H3 in TOV112D cells, which has low endogenous expression of B7-H3, resulted in the opposite effects, leading to increased glycolysis and mitochondrial respiration, increased STAT3 phosphorylation, increased migration, and increased resistance to carboplatin. We also performed RNA-seq analysis of OV-90 B7-H3 WT and KO clones and found several signaling pathways involved in cell migration, adhesion, and inflammatory response. Finally, we found that the growth of OV-90 B7-H3 KO cells was dramatically defective in xenograft models using both athymic nude and SCID immunocompromised mice. These results suggest that tumor-intrinsic B7-H3 plays a critical role in the growth of ovarian cancer and warrants further investigation of therapeutic approaches blocking B7-H3 functions for the treatment of this deadly malignancy in women. Citation Format: Holly Taylor, Jaroslav Slamecka, Alla Musiyenko, Elaine Gavin, Tiffany S. Norton, Ileana Aragon, Taylor Young, Jennifer Scalici
ISSN:1078-0432
1557-3265
DOI:10.1158/1557-3265.OVCA17-B31