title: Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis.
abstract: B7-H3 (CD276), part of the B7 superfamily of immune checkpoint molecules, has been shown to have an immunomodulatory role. Its regulation, receptor and mechanism of action remain unclear. B7-H3 protein expression correlates with prostate cancer outcomes, and humanized monoclonal antibodies (that is, enoblituzumab) are currently being investigated for therapeutic use. Here we used genomic expression data to examine the relationship between B7-H3 mRNA expression and prostate cancer.
  
  
  
  Prostatectomy tissue from 2781 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Pairwise comparisons were used to identify significant associations between B7-H3 expression and clinicopathologic variables, and survival analyses were used to evaluate the prognostic significance of B7-H3. Pearson's correlation analyses were performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy at the B7-H3 locus was determined using chromatin immunoprecipitation (ChIP), and androgen-dependent expression changes in B7-H3 was evaluated by quantitative reverse transcription PCR in LNCaP cell lines. Oncomine was queried to evaluate B7-H3 expression in metastatic disease.
  
  
  
  B7-H3 mRNA expression was positively associated with higher Gleason score (P<0.001), tumor stage (P<0.001), and castrate resistant metastatic disease (P<0.0001). High B7-H3 expression correlated with the development of metastasis and prostate cancer specific mortality, but this was not significant on multi-variable analysis. B7-H3 expression correlated with ERG-positive disease (r=0.99) and AR expression (r=0.36). ChIP revealed an AR-binding site upstream of B7-H3, and the presence of androgens decreased B7-H3 expression in LNCaP suggesting potential direct AR regulation. Gene set enrichment analysis demonstrated an association of B7-H3 with androgen signaling as well as immune regulatory pathways.
  
  
  
  Higher B7-H3 expression correlates with Gleason grade, prostate cancer stage and poor oncologic outcomes in prostatectomy cohorts. B7-H3 expression appears to be related to androgen signaling as well as the immune reactome.
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: B
authors: B
authors: Benzon
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
authors: S G
authors: SG
authors: Zhao
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.|Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: M C
authors: MC
authors: Haffner
authors: GenomeDx Biosciences, Vancouver, BC, Canada.
authors: M
authors: M
authors: Takhar
authors: GenomeDx Biosciences, Vancouver, BC, Canada.
authors: N
authors: N
authors: Erho
authors: GenomeDx Biosciences, Vancouver, BC, Canada.
authors: K
authors: K
authors: Yousefi
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: P
authors: P
authors: Hurley
authors: The Vancouver Prostate Cancer Centre, Vancouver, BC, Canada.
authors: J L
authors: JL
authors: Bishop
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: J
authors: J
authors: Tosoian
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: K
authors: K
authors: Ghabili
authors: GenomeDx Biosciences, Vancouver, BC, Canada.
authors: M
authors: M
authors: Alshalalfa
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: S
authors: S
authors: Glavaris
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: B W
authors: BW
authors: Simons
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.|Department of Radiation Oncology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: P
authors: P
authors: Tran
authors: GenomeDx Biosciences, Vancouver, BC, Canada.
authors: E
authors: E
authors: Davicioni
authors: The Vancouver Prostate Cancer Centre, Vancouver, BC, Canada.|Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors: R J
authors: RJ
authors: Karnes
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.|Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: K
authors: K
authors: Boudadi
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.|Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: E S
authors: ES
authors: Antonarakis
authors: Department of Urology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
authors: E M
authors: EM
authors: Schaeffer
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.|Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: C G
authors: CG
authors: Drake
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
authors: F
authors: F
authors: Feng
authors: Department of Urology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors: A E
authors: AE
authors: Ross
mesh_terms: D060887:B7 Antigens / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D056747:Immunomodulation; D053208:Kaplan-Meier Estimate; D008024:Ligands; D008297:Male; D011379:Prognosis; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D060887:B7 Antigens; C423237:CD276 protein, human; D008024:Ligands; D011944:Receptors, Androgen