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.

Noviello, M., Manfredi, F., Ruggiero, E., Perini, T., Oliveira, G., Cortesi, F., et al. (2019). Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. NATURE COMMUNICATIONS, 10(1) [10.1038/s41467-019-08871-1].

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

Gambacorta V.;
2019

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.
Articolo in rivista - Articolo scientifico
Adult; Antigens, CD; Antineoplastic Agents; Bone Marrow Cells; CTLA-4 Antigen; Female; Glucocorticoid-Induced TNFR-Related Protein; Hepatitis A Virus Cellular Receptor 2; Humans; Immunologic Memory; Leukemia, Myeloid, Acute; Male; Middle Aged; Programmed Cell Death 1 Receptor; Receptors, KIR; Recurrence; Remission Induction; Retrospective Studies; Signal Transduction; Signaling Lymphocytic Activation Molecule Family; T-Lymphocytes; Transplantation, Homologous; Clonal Anergy; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cell Transplantation
English
2019
10
1
1065
none
Noviello, M., Manfredi, F., Ruggiero, E., Perini, T., Oliveira, G., Cortesi, F., et al. (2019). Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. NATURE COMMUNICATIONS, 10(1) [10.1038/s41467-019-08871-1].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/240709
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