Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9-14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9-14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ-producing and IL2-producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients.

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia / Forghieri, Fabio; Riva, Giovanni; Lagreca, Ivana; Barozzi, Patrizia; Vallerini, Daniela; Morselli, Monica; Paolini, Ambra; Bresciani, Paola; Colaci, Elisabetta; Maccaferri, Monica; Gilioli, Andrea; Nasillo, Vincenzo; Messerotti, Andrea; Pioli, Valeria; Arletti, Laura; Giusti, Davide; Bettelli, Francesca; Celli, Melania; Donatelli, Francesca; Corradini, Giorgia; Basso, Sabrina; Gurrado, Antonella; Cellini, Monica; Trenti, Tommaso; Marasca, Roberto; Narni, Franco; Martelli, Maria Paola; Falini, Brunangelo; Potenza, Leonardo; Luppi, Mario; Comoli, Patrizia. - In: ONCOTARGET. - ISSN 1949-2553. - 10:8(2019), pp. 869-882. [10.18632/oncotarget.26617]

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia

Forghieri, Fabio;Riva, Giovanni;Lagreca, Ivana;Barozzi, Patrizia;Vallerini, Daniela;Morselli, Monica;Paolini, Ambra;Bresciani, Paola;Colaci, Elisabetta;Maccaferri, Monica;Gilioli, Andrea;Nasillo, Vincenzo;Messerotti, Andrea;Pioli, Valeria;Arletti, Laura;Giusti, Davide;Bettelli, Francesca;Celli, Melania;Donatelli, Francesca;Corradini, Giorgia;Marasca, Roberto;Narni, Franco;Potenza, Leonardo;Luppi, Mario;
2019

Abstract

Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9-14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9-14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ-producing and IL2-producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients.
10
8
869
882
Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia / Forghieri, Fabio; Riva, Giovanni; Lagreca, Ivana; Barozzi, Patrizia; Vallerini, Daniela; Morselli, Monica; Paolini, Ambra; Bresciani, Paola; Colaci, Elisabetta; Maccaferri, Monica; Gilioli, Andrea; Nasillo, Vincenzo; Messerotti, Andrea; Pioli, Valeria; Arletti, Laura; Giusti, Davide; Bettelli, Francesca; Celli, Melania; Donatelli, Francesca; Corradini, Giorgia; Basso, Sabrina; Gurrado, Antonella; Cellini, Monica; Trenti, Tommaso; Marasca, Roberto; Narni, Franco; Martelli, Maria Paola; Falini, Brunangelo; Potenza, Leonardo; Luppi, Mario; Comoli, Patrizia. - In: ONCOTARGET. - ISSN 1949-2553. - 10:8(2019), pp. 869-882. [10.18632/oncotarget.26617]
Forghieri, Fabio; Riva, Giovanni; Lagreca, Ivana; Barozzi, Patrizia; Vallerini, Daniela; Morselli, Monica; Paolini, Ambra; Bresciani, Paola; Colaci, Elisabetta; Maccaferri, Monica; Gilioli, Andrea; Nasillo, Vincenzo; Messerotti, Andrea; Pioli, Valeria; Arletti, Laura; Giusti, Davide; Bettelli, Francesca; Celli, Melania; Donatelli, Francesca; Corradini, Giorgia; Basso, Sabrina; Gurrado, Antonella; Cellini, Monica; Trenti, Tommaso; Marasca, Roberto; Narni, Franco; Martelli, Maria Paola; Falini, Brunangelo; Potenza, Leonardo; Luppi, Mario; Comoli, Patrizia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1187020
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