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Muraro, Elena (2013) IGHV1-69 as a promising candidate for the development of a shared immunotherapy to B-cell lymphomas. [Tesi di dottorato]

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Abstract (inglese)

B-cell Non-Hodgkin Lymphomas (B-NHL) are a heterogeneous group of cancers, broadly diffused worldwide and often relapsing after standard treatment and rituximab. Therapeutic vaccines targeting B-NHL idiotype (Id) represent a promising approach to maintain the complete response induced by standard treatments. However, customized idiotypic vaccination still remains a non-approved, experimental therapeutic option, mostly due to the personalized use and penalized by the lack of reliable clinical or biological markers of patient eligibility and responsiveness. Nevertheless, the molecular characterization of different lymphoid tumor histotypes revealed a set of stereotyped immunoglobulins among distinct B-cell lymphoma types. On this ground, we focused our attention on the IGHV1-69 protein, frequently expressed in HCV-associated lymphomas, chronic lymphocytic leukaemia, and auto-immunity related lymphoproliferations, and we characterized the ex vivo immunogenicity of this protein.
Seventy IGHV1-69 sequences obtained from patients affected by different B-NHLs or pre-malignant lymphoproliferations were compared to design an optimized sequence characterized by the highest degree of similarity among studied cancers, and thus CDR3 hypervariable region free. Within this “immunogenically” optimized sequence, we identified 13 potential HLA class-I cytotoxic T lymphocyte (CTL) epitopes and synthesized the corresponding pentamers (Pent). We assessed by flow cytometry the presence and extent of epitope-specific T-cell responses in peripheral blood of patients with IGHV1-69+ B-cell lymphoproliferative disorders and healthy donors, and validated these data in IFN-γ ELISPOT (Enzyme-linked immunosorbent spot) assays. Finally, we boosted in vitro IGHV1-69-specific responses by stimulating peripheral blood lymphocytes (PBL) from donors and patients with different protocols for the generation of epitope-specific CTL cultures.
Interestingly, the IGHV1-69 Pent+ population observed in patients’ samples was generally larger than in donors, supporting the existence of spontaneous memory T-cell responses against IGHV1-69, at least for some HLA-restrictions. Surprisingly, in patients’ samples, IGHV1-69-recognizing T cells displayed higher IFN-γ release in ELISPOT assays compared to viral-specific T cells. Moreover, we obtained peptide-specific CTL lines, which showed a weak but specific lysis against peptide-pulsed targets, especially when derived from patients’ PBLs. In addition, we were able to generate IGHV1-69-epitope specific CTL clones from healthy donors CD8+ T cells, employing synthetic artificial APC, developed to elicit and expand low-avidity tumor-directed human CTL lines. Finally, IGHV1-69-induced CTL lines showed specific lysis also towards an IGHV1-69 naturally expressing cell line, suggesting that IGHV1-69 memory T-cell responses could be boosted for therapeutic purposes.
These results show that IGHV1-69 constitutes a potential target for the development of a subset-specific Id vaccine. Furthermore, multimer (tetramers and pentamers) and ELISPOT immune-monitoring may partially overcome the main limitations of current Id-targeting vaccinations and further improve their clinical efficacy.

Abstract (italiano)

I Linfomi Non-Hodgkin a cellule-B (B-NHL) rappresentano un gruppo eterogeneo di patologie, ampiamente diffuse nel mondo e caratterizzate da frequenti ricadute in seguito a trattamenti standard o terapia con rituximab. Vaccini terapeutici che hanno come bersaglio l’Idiotipo (Id) dei B-NHL, costituiscono un approccio promettente nel mantenere la risposta completa indotta con trattamenti standard. Tuttavia, i vaccini idiotipici personalizzati rappresentano ancora un approccio terapeutico sperimentale e non approvato su larga scala, principalmente perché paziente-specifici e perché privi di marcatori attendibili per l’identificazione di pazienti elegibili e di risposta alla terapia. Ciononostante, la caratterizzazione molecolare di differenti istotipi di tumori di origine linfoide, ha rivelato la presenza di una serie di immunoglobuline stereotipate anche fra linfomi di diverso tipo. Su questi presupposti, abbiamo focalizzato la nostra attenzione sulla proteina IGHV1-69, frequentemente espressa in linfomi associati all’infezione da HCV, nella leucemia linfatica cronica (CLL) e in linfoproliferazioni associate ad auto-immunità, e abbiamo valutato in vitro l’immunogenicità di questa proteina.
Inizialmente, abbiamo confrontato 70 sequenze relative alla proteina IGHV1-69 e ottenute da pazienti affetti da differenti B-NHLs o linfoproliferazioni pre-maligne, allo scopo di ideare una sequenza ottimizzata, caratterizzata dal maggior grado di similarità fra i tumori presi in esame, e pertanto priva della regione ipervariabile CDR3. All’interno di questa nuova sequenza, abbiamo identificato 13 epitopi potenzialmente riconoscibili da linfociti T citotossici (CTLs) nell’ambito di 7 alleli HLA di classe I, e abbiamo sintetizzato i corrispondenti pentameri (Pent). Tramite citofluorimetria a flusso abbiamo quindi valutato la presenza di risposte T-cellulari specifiche per gli epitopi derivati da IGHV1-69, in campioni di sangue periferico ottenuti da pazienti affetti da linfoproliferazioni esprimenti IGHV1-69 e da donatori sani. Abbiamo inoltre validato questi dati tramite saggi ELISPOT (Enzyme-linked immunosorbent spot) per l’identificazione del rilascio di IFN-γ. Infine abbiamo stimolato in vitro le risposte specifiche per IGHV1-69, inducendo i linfociti del sangue periferico (PBLs) di donatori sani e pazienti, attraverso diversi protocolli per la generazione di colture CTL epitopo-specifiche.
E’ stato interessante osservare come nei campioni ottenuti da paziente la popolazione di linfociti T CD8+ positiva ai pentameri specifici per gli epitopi di IGHV1-69 sia risultata generalmente più numerosa della corrispondente popolazione osservata in donatori sani. Questo dato supporta l’esistenza di risposte memoria T cellulari nei confronti di IGHV1-69, almeno in alcune restrizioni HLA. Inoltre, nei campioni ottenuti da paziente le cellule T specifiche per gli epitopi di IGHV1-69 hanno rivelato in saggi ELISPOT un maggior rilascio di IFN-γ rispetto ai linfociti T specifici per epitopi virali. In aggiunta, stimolando parallelamente PBLs di donatori sani e pazienti, abbiamo ottenuto linee CTL peptide-specifiche, in grado di riconoscere debolmente, ma in modo specifico target caricati con il peptide d’interesse, soprattutto quando derivate da PBLs di pazienti. Inoltre, tramite l’utilizzo di antigen-presenting cells artificiali, prodotte allo scopo di indurre ed espandere linee CTL caratterizzare da bassa affinità nei confronti di antigeni tumorali, abbiamo anche generato cloni CTL specifici per un epitopo di IGHV1-69 a partire da linfociti T CD8+ di donatori. Infine, si è evidenziato che colture CTLs indotte in seguito a stimolo con epitopi derivanti da IGHV1-69, sono in grado di riconoscere in modo specifico una linea cellulare naturalmente esprimente IGHV1-69, suggerendo in questo modo che le risposte memoria T-cellulari specifiche per IGHV1-69, possano essere stimolate ed espanse a scopi terapeutici.
Questi risultati dimostrano che IGHV1-69 costituisce un target potenziale per lo sviluppo di un vaccino Id applicabile su un sottogruppo di linfomi a cellule B. Inoltre, l’immunomonitoraggio tramite marcatura con multimeri (tetrameri o pentameri) e saggi ELISPOT potrebbe eludere almeno parzialmente i principali limiti degli attuali vaccini idiotipici, al fine di incrementare ulteriormente la loro efficacia clinica.

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Tipo di EPrint:Tesi di dottorato
Relatore:Dolcetti, Riccardo
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:28 Gennaio 2013
Anno di Pubblicazione:28 Gennaio 2013
Informazioni aggiuntive:L'attività di ricerca descritta in questa tesi di dottorato è stata svolta presso l'Unità di Bioimmunoterapie dei Tumori umani del Centro di Riferimento Oncologico di Aviano (PN), e presso il Dipartimento di Immunologia dell'Università di Tubinga (Germania).
Parole chiave (italiano / inglese):B-cell Non Hodgkin's Lymphoma, Idiotypic vaccine, Immunotherapy, Immune monitoring
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:5595
Depositato il:16 Ott 2013 11:23
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