Intraprostatic inflammation and FoxP3, a marker of Regulatory T cells, increase with age in benign prostate biopsies irrespective of clinical indication: placebo arm of the Prostate Cancer Prevention Trial (PCPT)

Background : Intraprostatic inflammation is suspected to contribute to prostate cancer pathogenesis. Prostate cancer has the steepest age-related rise in incidence in solid cancers, and inflammation is thought to increase with age. But prostate tissue is typically obtained only from men with clinical indications, e.g., elevated plasma prostate-specific antigen (PSA). Associations between age and inflammation could be biased, given that PSA concentration increases with age, prompting biopsy. Thus, we used benign prostate tissue collected irrespective of indication to assess the association between age and intraprostatic inflammation and abundance of immune cells. Methods : We performed a cross-sectional analysis in a subset of men of the PCPT placebo arm. Using slides containing biopsy cores (mean 4) from protocol-prompted end-of-study prostate biopsies at Year 7, we visually assessed the presence and extent of inflammation and quantified immunohistochemistry staining for CD4 (CD4+ T cells), CD8 (CD8+ T cells), CD68 (macrophages), FoxP3 (T regulatory cells), and c-KIT (mast cells) using a score (0: none - 4: extensive). Scores were weighted by total number of cores per man. Associations between age (continuous or quartiles) and inflammation measures (any core inflamed vs none; all or some cores inflamed vs none; mean percent tissue inflamed ≥3% or <3% vs 0%) were estimated using logistic regression. Associations between age and immune cell marker scores (continuous) were estimated using linear regression. Estimates were adjusted for race, BMI, smoking, physical activity, education, diabetes, statin use, and aspirin use. Results : Participants (N=357) were 62 to 85 years of age at biopsy (median 70, IQR 65-74). Older age was associated with presence of inflammation [Q4 of age vs Q1: OR, 2.3; 95% CI, 1.1-4.9, p-trend across age, 0.003]. Positive associations were also observed with having some [Q4 OR, 2.1; 95% CI, 1.0-4.3] or all cores inflamed [Q4 OR, 7.8; 95% CI, 2.0-30.6]. Age was also associated with having ≥3% mean tissue with inflammation [Q4 OR, 2.6; 95% CI, 1.2-6.0, p-trend, 0.006]. Age was positively associated with FoxP3 score [p-value, 0.01], but not with any other immune cell markers. Associations were slightly attenuated when excluding men with PSA >4 ng/mL, diagnosed with prostate cancer, or who received for-cause biopsy. Conclusion : Age is associated with increasing presence and extent of intraprostatic inflammation in biopsies taken irrespective of indication. Consistent with findings in circulation, prevalence of T regulatory cells in prostate biopsies increased with age. Findings may inform the etiologic pathway, mediated by inflammation, between increasing age and prostate cancer. Funding: P50 DK082998, U01 CA182883, UG1CA189974, T32 CA09314, R01 CA255349, DOD.