Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT
Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT
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DOI：
10.1038/s41467-019-08871-1
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发表时间：
2019-03-25
影响因子：
16.6
通讯作者：
Bonini, Chiara
中科院分区：
文献类型：
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作者：
Noviello, Maddalena;Manfredi, Francesco;Bonini, Chiara
异基因造血干细胞移植（HSCT）治疗急性髓系白血病（AML）后死亡的主要原因是疾病复发。我们研究了32例HSCT后复发（中位数251天）或维持完全缓解（CR;中位数1年）的AML患者骨髓（BM）浸润T细胞上抑制性受体（IR; PD-1/CTLA-4/TIM-3/LAG-32 B4/KLRG 1/GITR）的表达。复发患者中早期分化记忆干细胞（T-SCM）和中央记忆BM-T细胞表达多重IR的比例高于CR患者。复发时耗尽的BM-T细胞显示出有限的TCR库、受损的效应子功能和白血病反应特异性。在57例患者中，早期检测到严重衰竭（PD-1（+）Eomes（+）T-bet（-））BM-T-SCM可预测复发。因此，白血病特异性T细胞在易于复发的患者中显示耗竭标记，而在维持长期CR的患者中不存在。这些结果强调了广泛的，虽然可逆的，免疫功能障碍的骨髓中的AML患者HSCT后复发，并提出了新的治疗机会的疾病。
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.