Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Maddalena Noviello; Francesco Manfredi; Eliana Ruggiero; Tommaso Perini; Giacomo Oliveira; Filippo Cortesi; Pantaleo De Simone; Cristina Toffalori; Valentina Gambacorta; Raffaella Greco; Jacopo Peccatori; Monica Casucci; Giulia Casorati; Paolo Dellabona; Masahiro Onozawa; Takanori Teshima; Marieke Griffioen; Constantijn J.M. Halkes; J. H.F. Falkenburg; Friedrich Stölzel; Heidi Altmann; Martin Bornhäuser; Miguel Waterhouse; Robert Zeiser; Jürgen Finke; Nicoletta Cieri; Attilio Bondanza; Luca Vago; Fabio Ciceri; Chiara Bonini

doi:10.1038/s41467-019-08871-1

Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Maddalena Noviello, Francesco Manfredi, Eliana Ruggiero, Tommaso Perini, Giacomo Oliveira, Filippo Cortesi, Pantaleo De Simone, Cristina Toffalori, Valentina Gambacorta, Raffaella Greco, Jacopo Peccatori, Monica Casucci, Giulia Casorati, Paolo Dellabona, Masahiro Onozawa, Takanori Teshima, Marieke Griffioen, Constantijn J.M. Halkes, J. H.F. Falkenburg, Friedrich StölzelHeidi Altmann, Martin Bornhäuser, Miguel Waterhouse, Robert Zeiser, Jürgen Finke, Nicoletta Cieri, Attilio Bondanza, Luca Vago, Fabio Ciceri, Chiara Bonini

Research output: Contribution to journal › Article

Abstract

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (T _SCM ) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1 ⁺ Eomes ⁺ T-bet ⁻ ) BM-T _SCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.

Original language	English
Article number	1065
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08871-1
Publication status	Published - Dec 1 2019

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Noviello, M., Manfredi, F., Ruggiero, E., Perini, T., Oliveira, G., Cortesi, F., De Simone, P., Toffalori, C., Gambacorta, V., Greco, R., Peccatori, J., Casucci, M., Casorati, G., Dellabona, P., Onozawa, M., Teshima, T., Griffioen, M., Halkes, C. J. M., Falkenburg, J. H. F., ... Bonini, C. (2019). Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. Nature Communications, 10(1), [1065]. https://doi.org/10.1038/s41467-019-08871-1

Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. / Noviello, Maddalena; Manfredi, Francesco; Ruggiero, Eliana; Perini, Tommaso; Oliveira, Giacomo; Cortesi, Filippo; De Simone, Pantaleo; Toffalori, Cristina; Gambacorta, Valentina; Greco, Raffaella; Peccatori, Jacopo; Casucci, Monica; Casorati, Giulia ; Dellabona, Paolo; Onozawa, Masahiro; Teshima, Takanori; Griffioen, Marieke; Halkes, Constantijn J.M.; Falkenburg, J. H.F.; Stölzel, Friedrich; Altmann, Heidi; Bornhäuser, Martin; Waterhouse, Miguel; Zeiser, Robert; Finke, Jürgen; Cieri, Nicoletta; Bondanza, Attilio; Vago, Luca ; Ciceri, Fabio ; Bonini, Chiara.

In: Nature Communications, Vol. 10, No. 1, 1065, 01.12.2019.

Research output: Contribution to journal › Article

Noviello, M, Manfredi, F, Ruggiero, E, Perini, T, Oliveira, G, Cortesi, F, De Simone, P, Toffalori, C, Gambacorta, V, Greco, R, Peccatori, J, Casucci, M, Casorati, G , Dellabona, P, Onozawa, M, Teshima, T, Griffioen, M, Halkes, CJM, Falkenburg, JHF, Stölzel, F, Altmann, H, Bornhäuser, M, Waterhouse, M, Zeiser, R, Finke, J, Cieri, N, Bondanza, A, Vago, L , Ciceri, F & Bonini, C 2019, 'Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT', Nature Communications, vol. 10, no. 1, 1065. https://doi.org/10.1038/s41467-019-08871-1

Noviello, Maddalena ; Manfredi, Francesco ; Ruggiero, Eliana ; Perini, Tommaso ; Oliveira, Giacomo ; Cortesi, Filippo ; De Simone, Pantaleo ; Toffalori, Cristina ; Gambacorta, Valentina ; Greco, Raffaella ; Peccatori, Jacopo ; Casucci, Monica ; Casorati, Giulia ; Dellabona, Paolo ; Onozawa, Masahiro ; Teshima, Takanori ; Griffioen, Marieke ; Halkes, Constantijn J.M. ; Falkenburg, J. H.F. ; Stölzel, Friedrich ; Altmann, Heidi ; Bornhäuser, Martin ; Waterhouse, Miguel ; Zeiser, Robert ; Finke, Jürgen ; Cieri, Nicoletta ; Bondanza, Attilio ; Vago, Luca ; Ciceri, Fabio ; Bonini, Chiara. / Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. In: Nature Communications. 2019 ; Vol. 10, No. 1.

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abstract = " The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (T SCM ) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1 + Eomes + T-bet − ) BM-T SCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease. ",

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