Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer.

Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a "viral mimicry" response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8+ T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies.

Our study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strategies to sensitize prostate cancer to immunotherapies.

Cancer research communications. 2022 Jul 25*** epublish ***

Mohammadreza Alizadeh-Ghodsi, Katie L Owen, Scott L Townley, Damien Zanker, Samuel P G Rollin, Adrienne R Hanson, Raj Shrestha, John Toubia, Tessa Gargett, Igor Chernukhin, Jennii Luu, Karla J Cowley, Ashlee Clark, Jason S Carroll, Kaylene J Simpson, Jean M Winter, Mitchell G Lawrence, Lisa M Butler, Gail P Risbridger, Benjamin Thierry, Renea A Taylor, Theresa E Hickey, Belinda S Parker, Wayne D Tilley, Luke A Selth

Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia., Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia., Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., South Australian Health and Medical Research Institute, Adelaide, SA, Australia., ARC Centre of Excellence in Convergent Bio and Nano Science and Technology, University of South Australia, Frome Road, Adelaide, SA, Australia.