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Provenzano, Maurizio (2009) Impaired immune pro-inflammatory cytokine profiling in
prostate cancer patients upon induction using peptides within
polyomavirus BK LTag-p53 binding regions.
[Ph.D. thesis]

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Abstract (english)

Prostate cancer (PCa) is a leading cause of cancer death in men. Nearly one third of annually new diagnosed cancers are prostate tumors. A contemporary model for prostate cancer induction and progression should include the potential contribution of inflammation to the development of preneoplastic or neoplastic lesions.
Human Polyomavirus BK (BKV) has been associated to pre-early stages of cancer in the urinary tract and it is postulated to play an important role in the pathogenesis of prostate cancer.
The BKV oncogenic effect appears to be highly associated to the activity of its main regulatory protein Large Tumor antigen (L-Tag) because of this antigen capability to bind and inactivate the products of tumor suppressor genes.
The involvement of BKV L-Tag in the alteration of critical pathways of the human cell cycle together with the detection and expression of BKV L-Tag sequences in preneoplastic prostate tissues prompted us to investigate the role of this viral antigen as target of cellular immune surveillance in prostate cancer.
Our previous results suggest that specific HLA-A*0201-associated BKV L-Tag candidate peptides nesting within regions responsible for L-Tag binding to p53 could efficiently be used to test the immune response in HLA-A*0201+ BKV seropositive donors.
In this study we propose a comprehensive characterization of an epitope specific T cell response against BKV L-Tag in BKV-experienced patients bearing either PCa or benign prostate hyperplasia (BPH), as compared to gender-matched healthy donors. The specific aim of this study is to test the hypothesis whether an inefficient immune responsiveness to antigens specifically expressed by oncogenic viruses located in the urinary tract may define a role for BKV L-Tag immune surveillance in organ specific tumorigenesis and subsequent neoplastic progression. Furthermore, we want to test if a systemic boosting of T cells from prostate cancer patients using immunogenic peptides within BKV L-Tag regions prevalently binding products of tumor suppressor genes (i.e. p53) and highly expressed in cancer cells would implement a T cell immune response in favor to a pro-inflammatory immune activity. We thus want to fully characterize the functional features of BKV specific T cell immune response elicited by L-Tag in patients bearing PCa.

Abstract (italian)

Il carcinoma prostatico rappresenta la seconda causa di morte piu’ importante nel mondo tra tutti i tumori dell’uomo. Circa un terzo dei nuovi casi di tumore diagnosticati annualmente nei soggetti maschi adulti, sono carcinomi prostatici. Un modello attuale riguardante l’insorgenza e la progressione del carcinoma prostatico dovrebbe includere il potenziale contributo dell’infiammazione come stimolo iniziale di lesioni preneoplastiche. Il virus del polioma umano BK è stato associato a stadi iniziali dei tumori dell’apparato urogenitale e si è postulato che il virus stesso giochi un ruolo importante nella patogenesi del carcinoma prostatico. La capacità oncogenica del virus BK è fortemente associata all’attività della sua principale proteina regolatoria, l’antigene tumorale Large T antigen, (L-Tag) data la capacità che ritiene la stessa di legare e inattivare i prodotti di geni oncosoppressori.
Il coinvolgimento della proteina regolatoria L-Tag del virus BK nell’alterazione di pathway enzimatici importanti del ciclo cellulare insieme con l’identificazione e l’espressione di sequenze della proteina regolatoria L-Tag in tessuti preneoplastici prostatici ci ha indotto ad investigare il ruolo che potrebbe assumere questo antigene virale come bersaglio della sorveglianza dello stato immunitario nei pazienti con carcinoma prostatico. Nostri precedenti risultati suggeriscono che determinati peptidi della proteina regolatoria L-Tag associati all’antigene HLA-A*0201, che posizionano all’interno di regioni del L-Tag responsabili per il legame con la proteina p53, possono efficientemente essere usati per testare la risposta immune in soggetti HLA-A*0201 positivi e sieropositivi per il virus BK. In questo studio proponiamo di caratterizzare più ampiamente la risposta immune contro peptidi della proteina regolatoria L-Tag in pazienti affetti da carcinoma prostatico e iperplasia benigna della prostata in confronto a soggetti sani dello stesso sesso. Lo scopo principale è quello di testare l’ipotesi riguardo alla quale un’inefficiente risposta immune contro antigeni, espressi da virus oncogeni presenti nel tratto urogenitale può definire un ruolo della sorveglianza dello stato immunitario contro la proteina regolatoria del virus BK nell’ambito della trasformazione tumorale dell’organo prostata e relativa progressione neoplastica. In aggiunta, vogliamo testare se una stimolazione sistematica di cellule di pazienti affetti da carcinoma prostatico usando peptidi della proteina regolatoria L-Tag ritenuti immunogeni in quanto derivanti da parti dell’antigene deputate al legame con proteine di geni oncosoppressori e prevalentemente espressi in cellule tumorali, possa implementare la risposta immune cellulo-mediata. Vogliamo dunque ampiamente analizzare le caratteristiche funzionali della risposta immune contro il virus BK in pazienti affetti da carcinoma prostatico.

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EPrint type:Ph.D. thesis
Tutor:Palu', Giorgio
Ph.D. course:Ciclo 21 > Corsi per il 21simo ciclo > VIROLOGIA E BIOTECNOLOGIE MICROBICHE
Data di deposito della tesi:30 January 2009
Anno di Pubblicazione:2009
Key Words:polyomavirus BK, prostate cancer, immunogenic peptide, regulatory T cells
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > pre 2012 Dipartimento di Istologia, Microbiologia e Biotecnologie Mediche
Codice ID:1731
Depositato il:30 Jan 2009
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