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.
|Original language||English (US)|
|Number of pages||12|
|State||Published - Jun 15 2022|
Bibliographical noteFunding Information:
Ashley E. Ross reports personal fees and honoraria from Veracyte, Astellas, Bayer, Pfizer, Blue Earth, Myovant, and Janssen outside the submitted work. Mary‐Ellen Taplin reports honoraria from AstraZeneca, AbbVie, Astellas, Bauer, Blue Earth, Constellation, Celegene, Epizyme, GlaxoSmithKline, Incyte, Janssen, Myovant, Roviant, UpToDate, the University of Pittsburgh, and the American Society for Clinical Oncology; and participation on a data safety monitoring board or advisory board for Clovis, Pfizer, and Myovant outside the submitted work. Nathan A. Lack reports personal fees from Nido Bioscience outside the submitted work. Angelo M. De Marzo reports research support from Janssen and Myriad during the conduct of the study and personal fees from Cepheid and Merck outside the submitted work. Emmanuel S. Antonarakis reports research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Merck, Bristol Myers Squibb, AstraZeneca, and Constellation; grants or contracts from AstraZeneca, Celgene, Clovis, and Sanofi; personal fees from Aikido Pharma, Blue Earth Diagnostics, Dendreon, EcoR1, KeyQuest Health, Janssen, Pfizer, and Projects in Knowledge; is a co‐inventor of an AR‐V7 biomarker technology that has been licensed to Qiagen; and reports participation on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Constellation, Curium, Eli Lilly and Company, Exact Sciences, Foundation Medicine, Invitae, Ismar, Merck, Orion, Sanofi, and Tempus outside the submitted work. Corinne E. Joshu reports institutional grants or contracts from the American Cancer Society and the National Institutes of Health outside the submitted work. Eugene Shenderov reports institutional research funding from Macrogenics and personal fees from Biopharma, Inc, Firstthough.IO, and Guidepoint Global outside the submitted work. Tamara L. Lotan reports research support from Roche/Ventana, DeepBio, and Myriad Genetics and support for attending meetings and/or travel from the Prostate Cancer Foundation outside the submitted work. The remaining authors made no disclosures.
This research was supported in part by 2 Health Disparity Research Awards from the Congressionally Directed Medical Research Programs‐Prostate Cancer Research Program (CDMRP‐PCRP) (W81XWH‐15‐1‐0661 to Edward M. Schaeffer and Tamara L. Lotan; W81XWH‐17‐1‐0286 to Karen S. Sfanos and Tamara L. Lotan). Additional funding and resources were provided by the National Institutes of Health/National Cancer Institute Prostate Specialized Centers Research Excellence (grant P50CA58236) and a National Cancer Institute Cancer Center Support grant (5P30CA006973‐52). Eugene Shenderov was supported by a Prostate Cancer Foundation Young Investigator Award and Congressionally Directed Medical Research Programs‐Prostate Cancer Research Program grant (W81XWH‐19‐1‐0511). Adriana A. Mendes was supported by a grant from the National Cancer Institute (T32CA193145).
© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.
- African American
- B7 homolog 3 (B7-H3)
- T cells
- androgen receptor (AR)
- prostatic adenocarcinoma
- tumor-infiltrating lymphocytes
PubMed: MeSH publication types
- Journal Article