Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer

• Published in: NPJ precision oncology Vol. 6; no. 1; pp. 80 - 6
• Main Authors: Shi, Xiaolei, Day, Abderrahman, Bergom, Hannah E., Tape, Sydney, Baca, Sylvan C., Sychev, Zoi E., Larson, Gabrianne, Bozicevich, Asha, Drake, Justin M., Zorko, Nicholas, Wang, Jinhua, Ryan, Charles J., Antonarakis, Emmanuel S., Hwang, Justin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 692/4028/67/589/466; 692/4028/67/69; Algorithms; Androgens; Antibodies; Antigens; Brief Communication; Cancer Research; Datasets; DNA methylation; Gene Therapy; Genes; Human Genetics; Immunotherapy; Internal Medicine; Medicine; Medicine & Public Health; Metastasis; Oncology; Patients; Precision medicine; Prostate cancer; Statistical significance; Tumors
• ISSN: 2397-768X; 2397-768X
• DOI: 10.1038/s41698-022-00323-2

B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was associated with resistance signaling pathways. Using a machine-learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes molecular profiles and epigenetic regulation of B7-H3-expressing mCRPC tumors, which informs optimal precision-oncology approaches for mCRPC patients.