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 Bozicevich; Justin M Drake; Nicholas Zorko; Jinhua Wang; Charles J Ryan; Emmanuel S Antonarakis; Justin Hwang

doi:10.1038/s41698-022-00323-2

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

NPJ Precis Oncol. 2022 Nov 2;6(1):80. doi: 10.1038/s41698-022-00323-2.

Authors

Xiaolei Shi¹, Abderrahman Day^{1

2}, Hannah E Bergom^{1

2}, Sydney Tape^{1

2}, Sylvan C Baca³, Zoi E Sychev⁴, Gabrianne Larson⁴, Asha Bozicevich^{1

2}, Justin M Drake^{4

5

6}, Nicholas Zorko^{1

2

6}, Jinhua Wang⁷, Charles J Ryan^{1

8}, Emmanuel S Antonarakis^{1

2

6}, Justin Hwang^{9

10

11}

Affiliations

¹ Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
² Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
³ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁴ Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
⁵ Department of Urology, University of Minnesota, Minneapolis, MN, USA.
⁶ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
⁷ Institute for Health Informatics, University of Minnesota, Minneapolis, MN, USA.
⁸ Prostate Cancer Foundation, Santa Monica, CA, USA.
⁹ Department of Medicine, University of Minnesota, Minneapolis, MN, USA. jhwang@umn.edu.
¹⁰ Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA. jhwang@umn.edu.
¹¹ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. jhwang@umn.edu.

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.

Abstract

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