Differential patterns of large tumor antigen-specific immune responsiveness in patients with BK polyomavirus-positive prostate cancer or benign prostatic hyperplasia.
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 β1 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.
Oncology Research Unit, Division of Urology, University of Zurich and University Hospital, Zurich, Switzerland.
Giovanni
G
Sais
Stephen
S
Wyler
Tvrtko
T
Hudolin
Irina
I
Banzola
Chantal
C
Mengus
Lukas
L
Bubendorf
Peter J
PJ
Wild
Hans H
HH
Hirsch
Tullio
T
Sulser
Giulio C
GC
Spagnoli
Maurizio
M
Provenzano
D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000097:blood*; D000951:Antigens, Neoplasm / Q000276:immunology*; D001739:BK Virus / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011470:Prostatic Hyperplasia / Q000276:immunology / Q000473:pathology / Q000821:virology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000821:virology*; D014764:Viral Proteins / Q000276:immunology*
D000914:Antibodies, Viral; D000951:Antigens, Neoplasm; D016207:Cytokines; D014764:Viral Proteins