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Differential patterns of large tumor antigen-specific immune responsiveness in patients with BK polyomavirus-positive prostate cancer or benign prostatic hyperplasia.

ABSTRACT: The role of the polyomavirus BK (BKV) large tumor antigen (L-Tag) as a target of immune response in patients with prostate cancer (PCa) has not been investigated thus far. In this study, we comparatively analyzed humoral and cellular L-Tag-specific responsiveness in age-matched patients bearing PCa or benign prostatic hyperplasia, expressing or not expressing BKV L-Tag-specific sequences in their tissue specimens, and in non-age-matched healthy individuals. Furthermore, results from patients with PCa were correlated to 5-year follow-up clinical data focusing on evidence of biochemical recurrence (BR) after surgery (prostate specific antigen level of ?0.2 ng/ml). In peripheral blood mononuclear cells (PBMC) from patients with PCa with evidence of BR and BKV L-Tag-positive tumors, stimulation with peptides derived from the BKV L-Tag but not those derived from Epstein-Barr virus, influenza virus, or cytomegalovirus induced a peculiar cytokine gene expression profile, characterized by high expression of interleukin-10 (IL-10) and transforming growth factor ?1 and low expression of gamma interferon genes. This pattern was confirmed by protein secretion data and correlated with high levels of anti-BKV L-Tag IgG. Furthermore, in PBMC from these PCa-bearing patients, L-Tag-derived peptides significantly expanded an IL-10-secreting CD4(+) CD25(+(high)) CD127(-) FoxP3(+) T cell population with an effector memory phenotype (CD103(+)) capable of inhibiting proliferation of autologous anti-CD3/CD28-triggered CD4(+) CD25(-) T cells. Collectively, our findings indicate that potentially tolerogenic features of L-Tag-specific immune response are significantly associated with tumor progression in patients with BKV(+) PCa.

SUBMITTER: Sais G

PROVIDER: S-EPMC3421724 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Differential patterns of large tumor antigen-specific immune responsiveness in patients with BK polyomavirus-positive prostate cancer or benign prostatic hyperplasia.

Sais Giovanni G Wyler Stephen S Hudolin Tvrtko T Banzola Irina I Mengus Chantal C Bubendorf Lukas L Wild Peter J PJ Hirsch Hans H HH Sulser Tullio T Spagnoli Giulio C GC Provenzano Maurizio M

Journal of virology 20120530 16

The role of the polyomavirus BK (BKV) large tumor antigen (L-Tag) as a target of immune response in patients with prostate cancer (PCa) has not been investigated thus far. In this study, we comparatively analyzed humoral and cellular L-Tag-specific responsiveness in age-matched patients bearing PCa or benign prostatic hyperplasia, expressing or not expressing BKV L-Tag-specific sequences in their tissue specimens, and in non-age-matched healthy individuals. Furthermore, results from patients wit ...[more]

PMID: 22647697

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Project description:ObjectiveProstate cancer (PCa) is the second most common male malignancy globally. Prostate-specific antigen (PSA) is an important biomarker for PCa diagnosis. However, it is not accurate in the diagnostic gray zone of 4-10 ng/ml of PSA. In the current study, the performance of serum metabolomics profiling in discriminating PCa patients from benign prostatic hyperplasia (BPH) individuals with a PSA concentration in the range of 4-10 ng/ml was explored.MethodsA total of 220 individuals, including patients diagnosed with PCa and BPH within PSA levels in the range of 4-10 ng/ml and healthy controls, were enrolled in the study. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based non-targeted metabolomics method was utilized to characterize serum metabolic profiles of participants. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) methods were used for multivariate analysis. Receiver operating characteristic (ROC) curve analysis was performed to explore the diagnostic value of candidate metabolites in differentiating PCa from BPH. Correlation analysis was conducted to explore the relationship between serum metabolites and common clinically used fasting lipid profiles.ResultsSeveral differential metabolites were identified. The top enriched pathways in PCa subjects such as glycerophospholipid and glycerolipid metabolisms were associated with lipid metabolism. Lipids and lipid-like compounds were the predominant metabolites within the top 50 differential metabolites selected using fold-change threshold >1.5 or <2/3, variable importance in projection (VIP) > 1, and Student's t-test threshold p < 0.05. Eighteen lipid or lipid-related metabolites were selected including 4-oxoretinol, anandamide, palmitic acid, glycerol 1-hexadecanoate, dl-dihydrosphingosine, 2-methoxy-6Z-hexadecenoic acid, 3-oxo-nonadecanoic acid, 2-hydroxy-nonadecanoic acid, N-palmitoyl glycine, 2-palmitoylglycerol, hexadecenal, d-erythro-sphingosine C-15, N-methyl arachidonoyl amine, 9-octadecenal, hexadecyl acetyl glycerol, 1-(9Z-pentadecenoyl)-2-eicosanoyl-glycero-3-phosphate, 3Z,6Z,9Z-octadecatriene, and glycidyl stearate. Selected metabolites effectively discriminated PCa from BPH when PSA levels were in the range of 4-10 ng/ml (area under the curve (AUC) > 0.80). Notably, the 18 identified metabolites were negatively corrected with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and Apo-B levels in PCa patients; and some were negatively correlated with high-density lipoprotein cholesterol (HDL-C) and Apo-A levels. However, the metabolites were not correlated with triglycerides (TG).ConclusionThe findings of the present study indicate that metabolic reprogramming, mainly lipid metabolism, is a key signature of PCa. The 18 lipid or lipid-associated metabolites identified in this study are potential diagnostic markers for differential diagnosis of PCa patients and BPH individuals within a PSA level in the gray zone of 4-10 ng/ml.

Project description:BackgroundMale lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.MethodsImmunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (surgical BPH, S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging System and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot analysis. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN.ResultsOPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2, and IL6 in BHPrS-1, but not in epithelial cell lines.ConclusionsOPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.

Dataset Information

Differential patterns of large tumor antigen-specific immune responsiveness in patients with BK polyomavirus-positive prostate cancer or benign prostatic hyperplasia.

Publications

Differential patterns of large tumor antigen-specific immune responsiveness in patients with BK polyomavirus-positive prostate cancer or benign prostatic hyperplasia.

Similar Datasets

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