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 target of immune response in patients with prostate cancer (PCa) has not been investigated so far. In this study we have comparatively analyzed humoral and cellular L-Tag specific responsiveness in age matched patients bearing PCa or benign prostatic hyperplasia (BPH), 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) following surgery (PSA≥0.2ng/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 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 IL-10 and TGFβ-1 and a low expression of IFN-γ 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(-(dim))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.