Characterization of Immune Dysfunction and Identification of Prognostic Immune-Related Risk Factors in Acute Myeloid Leukemia
Characterization of Immune Dysfunction and Identification of Prognostic Immune-Related Risk Factors in Acute Myeloid Leukemia
复制标题
急性髓性白血病免疫功能障碍的特征和预后免疫相关危险因素的鉴定
DOI：
10.1158/1078-0432.ccr-19-3003
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发表时间：
2020-04-01
影响因子：
11.5
通讯作者：
Hu, Yu
中科院分区：
文献类型：
--
作者：
Tang, Lu;Wu, Jianghua;Hu, Yu
目的：本研究旨在提供对急性髓细胞白血病（AML）发展和治疗中纵向免疫景观的全面见解，这可能有助于预测预后并指导临床决策。实验设计：前瞻性收集了79例AML患者（诊断时或/和化疗后或复发时）和24例健康对照的血液样本。我们通过多参数流式细胞术对各种淋巴细胞进行了表型和功能分析，并研究了预后免疫相关的风险因素。结果：AML的免疫缺陷反映在T细胞和自然杀伤（NK）细胞中，而B细胞功能不受影响。CD 8 + T细胞和CD 4 + T细胞在诊断时均表现出衰老和衰竭的特征。NK功能障碍得到了NKG 2D和NKP 30过度成熟和下调的支持。活化的γδ T细胞通过PD-1上调和NKG 2D下调表现出高度活化甚至耗竭状态。化疗后的有效治疗反应与T和NK功能恢复相关。难治性和复发性患者表现出更严重的免疫损伤，选择性免疫特征明显与临床结局和生存率相关。PD-1在CD 8 + T细胞中的表达是总生存率和无事件生存率差的独立预测因素。结论：T细胞衰老和衰竭以及NK和γδ T细胞功能受损是AML免疫功能障碍的主要方面。血液样本的非侵入性免疫检测可用于预测治疗反应性、复发的高风险和不良预后。
Purpose: This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide clinical decisions. Experimental Design: Periphery blood samples from 79 patients with AML (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected. We performed phenotypic and functional analysis of various lymphocytes through multiparametric flow cytometry and investigated prognostic immune-related risk factors. Results: Immune defects in AML were reflected in T and natural killer (NK) cells, whereas B-cell function remained unaffected. Both CD8+ T and CD4+ T cells exhibited features of senescence and exhaustion at diagnosis. NK dysfunction was supported by excessive maturation and downregulation of NKG2D and NKP30. Diseased γδ T cells demonstrated a highly activated or even exhausted state through PD-1 upregulation and NKG2D downregulation. Effective therapeutic response following chemotherapy correlated with T and NK function restoration. Refractory and relapsed patients demonstrated even worse immune impairments, and selective immune signatures apparently correlated clinical outcomes and survival. PD-1 expression in CD8+ T cells was independently predictive of poor overall survival and event-free survival. Conclusions: T-cell senescence and exhaustion, together with impaired NK and γδ T-cell function, are dominant aspects involved in immune dysfunction in AML. Noninvasive immune testing of blood samples could be applied to predict therapeutic reactivity, high risk for relapse, and unfavorable prognosis.