Risk-associated alterations in marrow T cells in pediatric leukemia

Current management of childhood leukemia is tailored based on disease risk determined by clinical features at presentation. Whether properties of the host immune response impact disease risk and outcome is not known. Here we combine mass cytometry, single cell genomics and functional studies to characterize the bone marrow immune environment in children with B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia at presentation. T cells in leukemia marrow demonstrate evidence of chronic immune activation and exhaustion/dysfunction, with attrition of naïve T cells and TCF1+ stem-like memory T cells and accumulation of terminally-differentiated effector T cells. Marrow-infiltrating natural killer cells also exhibit evidence of dysfunction, particularly in myeloid leukemia. Properties of immune cells identified distinct immune phenotype-based clusters correlating with disease risk in acute lymphoblastic leukemia. High-risk immune signatures were associated with expression of stem-like genes on tumor cells. These data provide a comprehensive assessment of the immune landscape of childhood leukemias and identify targets potentially amenable to therapeutic intervention. These studies also suggest that properties of the host response with depletion of naïve T cells and accumulation of terminal-effector T cells may contribute to the biologic basis of disease risk. Properties of immune microenvironment identified here may also impact optimal application of immune therapies, including T cell-redirection approaches in childhood leukemia. Overall design: Examination of bone marrow immune cell transcriptomes in pediatric B-cell acute lymphoblastic leukemia patients (B-ALL: n=7), acute myeloid leukemia patients (AML: n=8), and healthy donors (n=4)

当前儿童白血病的临床管理均依据患者初诊时的临床特征所评估的疾病风险进行个体化定制。目前尚不明确宿主免疫应答的特征是否会对疾病风险及转归产生影响。本研究结合质谱流式细胞术（mass cytometry）、单细胞基因组学（single cell genomics）与功能实验，对初诊B细胞急性淋巴细胞白血病（B-cell acute lymphoblastic leukemia, B-ALL）及急性髓系白血病（acute myelogenous leukemia, AML）患儿的骨髓免疫微环境进行表征分析。白血病骨髓中的T细胞呈现慢性免疫激活与耗竭/功能失调特征，表现为初始T细胞及TCF1+干细胞样记忆T细胞的耗竭，以及终末分化效应T细胞的累积。骨髓浸润性自然杀伤（natural killer, NK）细胞同样存在功能失调现象，在髓系白血病患者中尤为显著。基于免疫细胞特征所鉴定出的不同免疫表型簇，与急性淋巴细胞白血病的疾病风险存在显著相关性。高风险免疫特征谱与肿瘤细胞上干细胞样基因的表达呈正相关。本研究数据全面刻画了儿童白血病的免疫微环境全貌，并鉴定出潜在可用于治疗干预的靶点。本研究同时提示，宿主免疫应答特征——即初始T细胞耗竭与终末效应T细胞累积——或可作为疾病风险的生物学基础。本次研究鉴定出的免疫微环境特征，或可指导儿童白血病免疫治疗（包括T细胞重定向疗法）的优化应用。实验设计：对儿科B细胞急性淋巴细胞白血病患者（B-ALL：n=7）、急性髓系白血病患者（AML：n=8）及健康对照者（n=4）的骨髓免疫细胞转录组进行检测分析。