Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer
Xiaolei Shi, Abderrahman Day, Hannah E. Bergom, Sydney Tape, Sylvan C. Baca, Zoi E. Sychev, Gabrianne Larson, Asha J. Bozicevich, Justin M. Drake, Nicholas A. Zorko, Jinhua Wang, Charles J. Ryan, Emmanuel S. Antonarakis, Justin H. Hwang
Abstract
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.