Abstract 556: L-Tag-driven systemic immune regulatory profile as a potential signature for polyomavirus BK involvement in prostate cancer
Authors: Sais Giovanni , Wyler Stephen , Hudolin Tvrtko , Banzola Irina , Mengus Chantal , Bubendorf Lukas , Hirsch Hans H. , Spagnoli Giulio C. , Sulser Tullio , Provenzano Maurizio 
Published: August 2012

Abstract
Background: Polyomavirus BK (BKV) large tumor antigen (L-Tag) contributes to oncogenesis by regulating crucial pathways of human cell cycle when non-permissive cells are infected. Therefore, L-Tag has been identified as an important target of immune surveillance in L-Tag expressing tumors. The role of L-Tag as a target of tumor immune surveillance in prostate cancer (PCa) patients has not been investigated so far. In this study we thus analyzed the immunological profile exerted by L-Tag peptide-specific induction in newly diagnosed PCa patients by means of BKV L-Tag serology and local molecular testing, and compared it to age-matched benign prostatic hyperplasia (BPH) patients. Methods: We enrolled 60 newly diagnosed PCa patients and 50 age-matched BPH. Detection of BKV L-Tag DNA was carried out in random punches from tumor areas of surgically excised specimens. BKV L-Tag seroprevalence was determined by enzyme immunoassay (EIA). Systemic immune-regulatory activity was tested upon BKV L-Tag peptide-pool induction and analyzed using cytokine gene expressions (qrt-PCR), antigen-specific regulatory T cell (Treg) characterization (flow cytometry) and immune-regulatory protein release (multiplex fluorescent bead immunoassay). Data were correlated to 5-year follow-up clinical information. Five-year follow-up after surgery was completed on 48/60 PCa patients. Biochemical recurrence (BR) with early censoring was defined as the first PSA ≤ 0.2ng/ml. Results: In peripheral blood mononuclear cells (PBMCs) from PCa patients with evidence of biochemical recurrence (BR) and BKV L-Tag positive lesions, BKV L-Tag peptide-pool, but not the Epstein Barr/Influenza virus/Cytomegalovirus (CEF) peptide-pool, induced a particular gene profile, which was characterized by high expression of IL-10 and TGFβ-1 and a low expression of IFN-γ and TNF-α genes. This signature was confirmed by protein secretion data and correlated with levels of anti-BKV L-Tag IgG activity. Furthermore, in these PCa patients the L-Tag peptide pool significantly boosted IL-10 secreting CD4+CD25+(high)/FoxP3+(high)/CD103+ T cells exerting suppressive functions on autologous effectors (CD4+, CD25− and CD8+ T cell fractions) by reducing cell proliferation and IFN-γ production. Conclusion: Significant associations between immune regulatory activity exerted by BKV L-Tag induction, BKV L-Tag DNA positive tumor lesions and IgG activity against L-Tag were observed in PCa patients. In detail, BR+ PCa patients shared features such as functional BKV L-Tag specific immune regulatory profile with marked BKV L-Tag positive lesion and strong L-Tag-specific IgG activity, thereby hinting at a potential BKV involvement in prostate cancer progression. Our findings are thus consistent with a systemic BKV L-Tag-related tolerogenic environment governing prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 556. doi:1538-7445.AM2012-556