Association of B7‐H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer

Abstract

Background B7 homolog 3 (B7‐H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD‐L1. Immunotherapies (antibodies, antibody‐drug conjugates, and chimeric antigen receptor T cells) targeting B7‐H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7‐H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7‐H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. Methods An automated, clinical‐grade immunohistochemistry assay was developed by to digitally quantify B7‐H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. Results B7‐H3 protein expression was significantly lower in self‐identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7‐H3 protein expression with ERG/ETS and PTEN status. B7‐H3 messenger RNA expression, but not B7‐H3 protein expression, was significantly correlated with regulatory (FOXP3‐positive) T‐cell density. Finally, androgen receptor activity scores were significantly correlated with B7‐H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7‐H3 protein expression. Conclusions The current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7‐H3 expression. Lay Summary B7‐H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7‐H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7‐H3 messenger RNA expression is correlated with the density of tumor T‐regulatory cells. Finally, in the first paired analysis of B7‐H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7‐H3 protein levels, suggesting that androgen signaling may positively regulate B7‐H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials.

Association of self-identified race and genetic ancestry with the immunogenomic landscape of primary prostate cancer

“…Median follow-up for the entire cohort was 6 years, and it was 6 years for BL and 7 years for WH patients. As previously reported for this cohort ( 33 ), self-identified race was highly correlated with percent African (Yoruba) ancestry (YRI), with rare exceptions ( Supplemental Figure 2 ).…”

“…In cases where most blocks were extensively involved by tumor, we sampled adjacent normal tissue from tumor-containing blocks, as long as it was > 3 mm from the tumor sample. Genetic ancestry estimation on this cohort was obtained through SNP array data (Global Screening Array v3, GSAv3), as previously published ( 33 ).…”

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

“…B7-H3 is regulated epigenetically in nasopharyngeal carcinoma 28 and glioblastoma 29 , via histone acetylation and DNA methylation at the promotor, respectively. The convergence between B7-H3 and AR signaling that we identified agreed with prior studies 30 . We thus sought to interrogate this mechanism of regulation through CHIP-seq data from both primary prostate cancer and mCRPC xenograft samples 31 , 32 .…”

“…Our findings established a mechanistic connection between B7-H3 expression and AR-related signaling in mCRPC. This may also hold true in high-risk localized prostate tumors, since B7-H3 immunostaining is reduced after intense neoadjuvant ADT given before radical prostatectomy 30 . Finally, the epigenetic modifications we found may act as surrogates to measure B7-H3 levels from noninvasive liquid biopsies that include circulating-tumor DNA from mCRPC patients 27 .…”

The Immunotherapy and Immunosuppressive Signaling in Therapy-Resistant Prostate Cancer

“…In addition, PTEN deficiency inhibits innate and adaptive immune responses by impairing the activation of type I IFN and NF-κB pathways [ 103 ], suppressing the antigen-presenting function of DCs, and the recruitment and activation of T and NK cells [ 104 , 105 ]. PTEN loss was also associated with the increased expression of the immunosuppressive molecules IDO1 and CD276 in prostate cancer tissue [ 102 , 105 , 106 ]. At the same time, the loss of PTEN was associated with the increased expression of a series of chemokines (CXCL12 and CXCL8), which indirectly caused the formation of an immunosuppressive TME in prostate cancer [ 107 , 108 ].…”