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Mainardi, Chiara (2017) Detection of an immunological response against TEL/AML1 fusion protein. [Tesi di dottorato]

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Abstract (inglese)

Immunotherapy represents a therapeutic option for subgroups of paediatric patients with leukaemia who, despite the impressing advances of the last decades in the field, still show a poor prognosis because of high risk-disease or relapse.
A deeper understanding of how the immune system physiologically recognizes and eradicates tumour cells is mandatory.
Peptidic antigens are of great interest in the field of immunotherapy because they could be used as vaccines to boost immunity.
TEL/AML1 mutant protein, whose sequence is known, is the result of a balanced t(12;21) translocation which generates a fusion gene. Peptides can be artificially synthetized from TEL/AML1 fusion protein and their HLA-binding capacity and immunogenicity can be predicted through bioinformatic tools.
This project aimed to investigate whether the excellent prognosis showed by patients who suffer from a B-lineage ALL harbouring the TEL/AML1 mutation could be related to an immune response against peptidic antigens derived from the TEL/AML1 mutant protein.
For such purpose, 8 priming experiments were performed with healthy donors’ leucocytes. Six experiments were carried out according to a dendritic cells-mediated protocol, whereas two experiments were performed according to a beads-mediated protocol. Successfully primed lymphocytes (identified by mean of intracellular cytokines production) were selected through flow cytometric sorting and single-cell seeded in order to get T-cell clones. This was possible in 3 out of 8 priming experiments. Growing T-cell clones were tested after stimulation with peptides (or through tetramer staining) but they did not show enough specificity.
We also tried to show an immune response against fusion peptides in peripheral blood leucocytes of patients who survived a TEL/AML1 positive B-lineage ALL, through exposure to peptides and a short course stimulation with cytokines.
We tested 22 patients, but unfortunately we weren’t able to show an answer against fusion peptides in any of them.
Possible reasons might be the lack of specificity of the activation markers we used to identify reactive cells, the not enough restrictive gates we used for sorting, the fact that the HLA super type B*07 (for which the restricted peptides had the best prediction score) was underrepresented in our patients’ cohort.
We suggest to perform further experiments using new activation markers, such as CD25 or PD-L1, or different techniques to identify reactive cells (such as Elispot), to use more restrictive gates for sorting and to exploit the beads priming protocol.
In order to sample such lymphocyte populations (i.e. antigen specific T-cells) with an extremely low frequency, a possibility may be collect repeatedly blood samples from the same patient at different time points.
Further studies are warranted to test the hypothesis of an autologous, spontaneously arising immune response against TEL/AML1 fusion peptides as reason for the good prognosis of TEL/AML1 positive leukaemia.
Another possible approach in order to validate fusion peptides might be to test them in a situation of HLA B*07 mismatch between lymphocytes and APCs. The clinical counterpart could be the generation of reactive T-cell clones, cloning of their TCR and its transduction in the patient’s or donor’s lymphocytes, the latter in the perspective of a post-hematopoietic stem cell transplantation adoptive immunotherapy.

Abstract (italiano)

L’immunoterapia costituisce un’opzione terapeutica per alcuni sottogruppi di pazienti con leucemia dell’età pediatrica i quali, nonostante i notevoli progressi degli ultimi decenni, ancora non mostrano una prognosi soddisfacente perché affetti da malattia ad alto rischio oppure da ricaduta.
Una comprensione più profonda di come il sistema immunitario fisiologicamente riconosce ed elimina le cellule tumorali è essenziale.
Gli antigeni peptidici sono di grande interesse nel settore dell’immunoterapia perché possono essere utilizzati come vaccini per potenziare l’immunità.
La proteina mutante TEL/AML1, la cui sequenza è nota, è il risultato di una traslocazione bilanciata t(12;21) che genera un gene di fusione. Dalla proteina di fusione TEL/AML1 si possono sintetizzare artificialmente peptidi, la cui capacità di legare le molecole HLA ed immunogenicità si può prevedere attraverso strumenti bioinformatici.
Questo progetto ha l’obiettivo di indagare se l’eccellente prognosi dei pazienti affetti da leucemia linfoblastica di linea B con la mutazione TEL/AML1 possa essere correlata ad una risposta immunologica nei confronti di peptide di fusion derivati dalla proteina mutante TEL/AML1.
A tale scopo, sono stati realizzati 8 esperimenti di priming con leucociti di donatori sani. Sei sono stati realizzati secondo un protocollo mediato da cellule dendritiche, mentre altri due esperimenti sono stati condotti secondo un protocollo mediato da beads. I linfociti responsivi al processo di priming (identificati mediante la produzione intracellulare di citochine) sono stati selezionati mediante sorting citofluorimetrico e coltivati a singola cellula in modo da ottenete cloni T-cellulari. Ciò è stato possibile in 3 esprimenti su 8. I cloni T-cellulari con evidenza di crescita sono stati testati dopo re-stimolazione con i peptidi (o mediante tetramer-staining) ma non hanno dimostrato sufficiente specificità-
Abbiamo inoltre provato a dimostrare una risposta immunologica nei confronti dei peptidi di fusione nei leucociti (da sangue periferico) di pazienti con leucemia linfoblastica di linea B TEL/AML1 positiva in remissione, mediante esposizione ai peptidi e una breve stimolazione con citochine. Sono stati testati 22 pazienti, ma purtroppo non è stato possibile evidenziare una risposta nei confronti dei peptidi di fusione in nessuno di loro.
Possibili spiegazioni potrebbero essere la mancanza di specificità dei marcatori di attivazione che sono stati utilizzati per identificare le cellule reattive, i gate non sufficientemente restrittivi utilizzati per il sorting, il fatto che il supertipo HLA B*07 (i peptidi B*07 ristretti avevano il migliore score predittivo) era sotto-rappresentato nella coorte di pazienti presa in esame.
Ci riproponiamo di realizzare ulteriori esperimenti utilizzando nuovi marcatori di attivazione, come CD25 o PD-L1, oppure differenti tecniche per identificare le cellule reattive (come l’Elispot), di usare gates più restrittivi per il sorting e di utilizzare esclusivamente il protocollo mediato da beads per il priming.
Per riuscire a includere nel campione popolazioni linfocitarie (cellule T antigene-specifiche) la cui frequenza è estremamente bassa, una possibilità potrebbe essere eseguire prelievi ematici ripetuti nel tempo nello stesso paziente.
Sono necessari ulteriori studi per testare l’ipotesi di una risposta immune autologa, spontanea, nei confronti dei peptidi di fusione TEL/AML1 come spiegazione della buona prognosi della leucemia linfoblastica di linea B TEL/AML1 positiva.
Un altro possibile approccio per validare i peptidi di fusione potrebbe essere quello di testarli in una situazione di HLA B*07 mismatch tra linfociti ed APCs. La ricaduta clinica potrebbe essere la generazione di cloni T-cellulari dalle cellule reattive al priming, il clonaggio del loro TCR e la sua transduzione nei linfociti del paziente o del suo donatore, in quest’ultimo caso nella prospettiva di un’immunoterapia adottiva post-trapianto di cellule staminali ematopoietiche.

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Tipo di EPrint:Tesi di dottorato
Relatore:Buldini, Barbara
Dottorato (corsi e scuole):Ciclo 29 > Corsi 29 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE SANITARIA
Data di deposito della tesi:30 Gennaio 2017
Anno di Pubblicazione:30 Gennaio 2017
Parole chiave (italiano / inglese):Haematopoietic stem cell transplantation/trapianto di cellule staminali ematopoietiche Immunotherapy/Immunoterapia Peptides/peptidi T-cell priming/Priming dei linfociti T Stem cell boost/Boost di cellule staminali Poor graft function/attecchimento non soddisfacente Extracorporeal photochemotherapy/fotochemioterapia extracorporea Graft-versus-host disease (GvHD)/malattia del trapianto contro l'ospite
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/15 Malattie del sangue
Area 06 - Scienze mediche > MED/06 Oncologia medica
Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:10070
Depositato il:06 Nov 2017 15:19
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