TY - JOUR
T1 - Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT
AU - Noviello, Maddalena
AU - Manfredi, Francesco
AU - Ruggiero, Eliana
AU - Perini, Tommaso
AU - Oliveira, Giacomo
AU - Cortesi, Filippo
AU - De Simone, Pantaleo
AU - Toffalori, Cristina
AU - Gambacorta, Valentina
AU - Greco, Raffaella
AU - Peccatori, Jacopo
AU - Casucci, Monica
AU - Casorati, Giulia
AU - Dellabona, Paolo
AU - Onozawa, Masahiro
AU - Teshima, Takanori
AU - Griffioen, Marieke
AU - Halkes, Constantijn J.M.
AU - Falkenburg, J. H.F.
AU - Stölzel, Friedrich
AU - Altmann, Heidi
AU - Bornhäuser, Martin
AU - Waterhouse, Miguel
AU - Zeiser, Robert
AU - Finke, Jürgen
AU - Cieri, Nicoletta
AU - Bondanza, Attilio
AU - Vago, Luca
AU - Ciceri, Fabio
AU - Bonini, Chiara
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-019-08871-1
DO - 10.1038/s41467-019-08871-1
M3 - Article
C2 - 30911002
AN - SCOPUS:85063578408
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1065
ER -