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

Fabio Forghieri, Giovanni Riva, Ivana Lagreca, Patrizia Barozzi, Daniela Vallerini, Monica Morselli, Ambra Paolini, Paola Bresciani, Elisabetta Colaci, Monica Maccaferri, Andrea Gilioli, Vincenzo Nasillo, Andrea Messerotti, Valeria Pioli, Laura Arletti, Davide Giusti, Francesca Bettelli, Melania Celli, Francesca Donatelli, Giorgia CorradiniSabrina Basso, Antonella Gurrado, Monica Cellini, Tommaso Trenti, Roberto Marasca, Franco Narni, Maria Paola Martelli, Brunangelo Falini, Leonardo Potenza, Mario Luppi, Patrizia Comoli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)869-882
Number of pages14
JournalOncotarget
Volume10
Issue number8
Publication statusPublished - Jan 1 2019

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Keywords

  • Acute myeloid leukemia
  • Immunity
  • NPM1 mutation
  • T cell therapy

ASJC Scopus subject areas

  • Oncology

Cite this

Forghieri, F., Riva, G., Lagreca, I., Barozzi, P., Vallerini, D., Morselli, M., Paolini, A., Bresciani, P., Colaci, E., Maccaferri, M., Gilioli, A., Nasillo, V., Messerotti, A., Pioli, V., Arletti, L., Giusti, D., Bettelli, F., Celli, M., Donatelli, F., ... Comoli, P. (2019). Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia. Oncotarget, 10(8), 869-882.