T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts.
T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts.
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DOI：
10.18632/oncotarget.12357
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发表时间：
2016-11-22
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影响因子：
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通讯作者：
Feuchtinger T
中科院分区：
文献类型：
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作者：
Feucht J;Kayser S;Gorodezki D;Hamieh M;Döring M;Blaeschke F;Schlegel P;Bösmüller H;Quintanilla-Fend L;Ebinger M;Lang P;Handgretinger R;Feuchtinger T
T细胞免疫疗法是复发性/难治性前体B细胞急性淋巴细胞白血病（ALL）的有希望的选择。我们研究了协同信号分子对CD 19/CD 3双特异性T细胞介导的T细胞抗白血病攻击的影响。对原发性CD 19 + ALL原始细胞（n≥10）和生理性CD 19 + CD 10+骨髓前体细胞筛选20种共信号分子。与生理细胞相比，PD-L1、PD-1、LAG-3、CD 40、CD 86、CD 27、CD 70和HVEM显示儿科ALL的刺激和抑制特征不同，PD-L1和CD 86是最突出的抑制和刺激标志物。复发性ALL患者（n=11）和Blinatumomab难治性ALL患者（n=5）的PD-L1升高。与生理对照相比，患者T细胞上的耗竭标志物（PD-1，TIM-3）显著更高。T细胞增殖和效应子功能是靶细胞依赖性的，并且与共信号分子的表达相关。阻断抑制性PD-1-PD-L和CTLA-4-CD 80/86通路增强了T细胞功能，而阻断共刺激性CD 28-CD 80/86相互作用显著降低了T细胞功能。Blinatumomab与抗PD-1抗体联合治疗是可行的，并在1例12岁难治性ALL患者中诱导了体内抗白血病应答。总之，ALL细胞通过表达共信号分子积极调节T细胞功能，并改变治疗性T细胞攻击ALL的疗效。白血病诱导的检查点分子的抑制性相互作用可以指导未来的T细胞疗法。
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers. PD-L1 was increased in relapsed ALL patients (n=11) and in ALLs refractory to Blinatumomab (n=5). Exhaustion markers (PD-1, TIM-3) were significantly higher on patients' T cells compared to physiologic controls. T-cell proliferation and effector function was target-cell dependent and correlated to expression of co-signaling molecules. Blockade of inhibitory PD-1-PD-L and CTLA-4-CD80/86 pathways enhanced T-cell function whereas blockade of co-stimulatory CD28-CD80/86 interaction significantly reduced T-cell function. Combination of Blinatumomab and anti-PD-1 antibody was feasible and induced an anti-leukemic in vivo response in a 12-year-old patient with refractory ALL. In conclusion, ALL cells actively regulate T-cell function by expression of co-signaling molecules and modify efficacy of therapeutic T-cell attack against ALL. Inhibitory interactions of leukemia-induced checkpoint molecules can guide future T-cell therapies.