Inflammatory infiltration is associated with AR expression and poor prognosis in hormone naïve prostate cancer

McAllister, M., Constancio, V., Patek, S., Gan, H., Bailey, P. , Wheadon, H. , Underwood, M., Leung, H. and Edwards, J. (2020) Inflammatory infiltration is associated with AR expression and poor prognosis in hormone naïve prostate cancer. Prostate, 80(15), pp. 1353-1364. (doi: 10.1002/pros.24064) (PMID:32846021)

Abstract

Background: Tumor microenvironment inflammatory infiltration is proposed as a protumorigenic mechanism for prostate cancer with proinflammatory cytokines stimulating androgen receptor (AR) activity. However, association with patient prognosis remains unclear. This study derives an inflammatory gene signature associated with AR expression and investigates CD3+ and CD8+ T‐lymphocyte infiltration association with AR and prognosis. Methods: Gene profiling of inflammatory related genes was performed on 71 prostate biopsies. Immunohistochemistry on 243 hormone‐naïve prostate cancers was performed for CD3, CD8, AR, and phosphorylated AR tumor expression. Results: Multiple proinflammatory genes were differentially expressed in association with high AR expression compared with low AR expression including PI3KCA and MAKP8 (adjusted P < .05). High CD3+ and high CD8+ infiltration associated with reduced cancer‐specific survival (P = .018 and P = .020, respectively). High CD3+ infiltration correlated with high tumor cytoplasmic AR expression and if assessed together, they associated with reduced cancer‐specific and 5‐year survival from 90% to 56% (P = .000179). High CD8+ cytotoxic infiltration associated with high androgen‐independent tumor nuclear AR serine 213 phosphorylation (correlation coefficient = 0.227; P = .003) and when assessed together associated with poor clinico‐pathological features including perineural invasion (P = .001). Multiple genes involved in proinflammatory signaling pathways are upregulated in high AR expressing prostate samples. Conclusion: T‐lymphocyte infiltration in hormone‐naïve disease associates with androgen‐independent driven disease and provides possible therapeutic targets to reduce transformation from hormone‐naïve to castrate‐resistant disease.

• Item Type: Articles
• Additional Information: Funding information: Prostate Cancer UK, Grant/Award Number: S14‐003.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leung, Professor Hing and Underwood, Mr Mark and Edwards, Professor Joanne and Wheadon, Professor Helen and Bailey, Dr Peter and McAllister, Milly and Patek, Mrs Samantha
• Authors: McAllister, M., Constancio, V., Patek, S., Gan, H., Bailey, P., Wheadon, H., Underwood, M., Leung, H., and Edwards, J.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Prostate
• Publisher: Wiley
• ISSN: 0270-4137
• ISSN (Online): 1097-0045
• Published Online: 26 August 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Prostate 80(15):1353-1364
• Publisher Policy: Reproduced under a Creative Commons Licence