Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy
Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy
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DOI：
10.1172/jci.insight.120974
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发表时间：
2018-11-02
期刊：
影响因子：
8
通讯作者：
Gojo, Ivana
中科院分区：
文献类型：
--
作者：
Knaus, Hanna A.;Berglund, Sofia;Gojo, Ivana
背景我们对急性髓系白血病（AML）中CD 8（+）T细胞功能障碍的表型和功能特征的了解有限。解读这些紊乱的T细胞功能状态以及它们如何受到诱导化疗的影响对于整合新的基于免疫的策略以恢复和维持抗白血病免疫是至关重要的。我们利用高维免疫表型、基因表达和功能研究来表征72例AML患者诊断时和诱导化疗后外周血和骨髓CD 8（+）T细胞的特征。我们的数据表明，T细胞功能紊乱的多个方面在AML诊断中起作用，其中衰竭和衰老是主要过程。治疗后，CD 8（+）T细胞的表型和转录谱在应答者和无应答者之间出现差异。对治疗的反应与共刺激T细胞信号传导途径的上调以及凋亡和抑制性T细胞信号传导途径的下调相关，指示T细胞功能的恢复。在功能研究中，AML原始细胞直接改变了CD 8（+）T细胞的活力、扩增、共信号传导和衰老标志物表达。这种CD 8（+）T细胞功能障碍在PD-1阻断或OX 40体外共刺激后部分可逆。我们的研究结果强调了AML在塑造CD 8（+）T细胞应答方面的独特性及其在化疗应答后的可塑性，为整合新的免疫疗法以增强抗白血病免疫力提供了令人信服的理由。
BACKGROUND. Our understanding of phenotypic and functional signatures of CD8(+) T cell dysfunction in acute myeloid leukemia (AML) is limited. Deciphering these deranged T cell functional states and how they are impacted by induction chemotherapy is essential for incorporation of novel immune-based strategies to restore and maintain antileukemia immunity.METHODS. We utilized high-dimensional immunophenotyping, gene expression, and functional studies to characterize peripheral blood and bone marrow CD8(+) T cells in 72 AML patients at diagnosis and after induction chemotherapy.RESULTS. Our data suggest that multiple aspects of deranged T cell function are operative in AML at diagnosis, with exhaustion and senescence being the dominant processes. Following treatment, the phenotypic and transcriptional profile of CD8(+) T cells diverged between responders and nonresponders. Response to therapy correlated with upregulation of costimulatory, and downregulation of apoptotic and inhibitory, T cell signaling pathways, indicative of restoration of T cell function. In functional studies, AML blasts directly altered CD8(+) T cell viability, expansion, co-signaling and senescence marker expression. This CD8(+) T cell dysfunction was in part reversible upon PD-1 blockade or OX40 costimulation in vitro.CONCLUSION. Our findings highlight the uniqueness of AML in sculpting CD8(+) T cell responses and the plasticity of their signatures upon chemotherapy response, providing a compelling rationale for integration of novel immunotherapies to augment antileukemia immunity.