Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response

• Published in: European urology 2017-05, Vol.71 (5), p.776-787
• Main Authors: Ylitalo, Erik Bovinder, Thysell, Elin, Jernberg, Emma, Lundholm, Marie, Crnalic, Sead, Egevad, Lars, Stattin, Pär, Widmark, Anders, Bergh, Anders, Wikström, Pernilla
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; ATP-Binding Cassette Sub-Family B Member 2 - genetics; ATP-Binding Cassette Sub-Family B Member 2 - immunology; Bone metastasis; Bone Neoplasms - genetics; Bone Neoplasms - immunology; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Case-Control Studies; Castration-resistance; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - immunology; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 3-alpha - genetics; HLA-A Antigens - genetics; HLA-A Antigens - immunology; Homeodomain Proteins - genetics; Humans; Immune response; Immunohistochemistry; Kallikreins - genetics; Male; Medicin och hälsovetenskap; Membrane Proteins - genetics; Metabolism; Middle Aged; Multivariate Analysis; Neoplasm Proteins - genetics; Oxidoreductases - genetics; Principal Component Analysis; Prostate cancer; Prostate-Specific Antigen - genetics; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - immunology; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Serine Endopeptidases - genetics; Transcription Factors - genetics; Urology
• ISSN: 0302-2838; 1873-7560; 1873-7560
• DOI: 10.1016/j.eururo.2016.07.033

Abstract Background Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives To identify molecular subgroups of PC bone metastases of relevance for therapy. Design, setting, and participants Fresh-frozen bone metastasis samples from men with CRPC ( n = 40), treatment-naïve PC ( n = 8), or other malignancies ( n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases ( n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease ( n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients ( n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation. Results and limitations The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes ( KLK2 , KLK3 , NKX3.1 , STEAP2 , TMPRSS2 ); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression ( HLA-A , TAP1 , and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient. Conclusions Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possi