Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice.
Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice.
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DOI：
10.3324/haematol.2019.238154
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发表时间：
2021-04-01
期刊：
影响因子：
10.1
通讯作者：
Seiffert M
中科院分区：
文献类型：
--
作者：
Hanna BS;Yazdanparast H;Demerdash Y;Roessner PM;Schulz R;Lichter P;Stilgenbauer S;Seiffert M
伊布鲁替尼是一种布鲁顿酪氨酸激酶(BTK)抑制剂，被批准用于治疗包括慢性淋巴细胞白血病(CLL)在内的多种B细胞恶性肿瘤。除了阻断B细胞受体信号和趋化因子受体介导的CLL细胞内已知的疾病驱动因素外，伊布鲁替尼还通过靶向髓系细胞中的BTK和T细胞中IL-2诱导的T细胞激酶(ITK)来影响CLL的微环境。这些非BTK效应被认为是伊布鲁替尼治疗慢性淋巴细胞性白血病成功的原因。通过采用Eμ-TCL1过继转移小鼠模型，我们观察到伊布鲁替尼有效地控制了白血病的发展，但也导致CD8+效应性T细胞数量显著减少，活化标志表达减少，增殖和效应器功能受损。使用T细胞受体(TCR)报告鼠的CD8+T细胞，我们证实这是由于伊布鲁替尼对TCR活性的直接影响，并证明通过CD28的共同刺激克服了这些影响。最有趣的是，伊布鲁替尼与体内针对PD-1/PD-L1轴的封闭抗体相结合，改善了CD8+T细胞效应器功能和CLL的控制。综上所述，这些数据强调了伊布鲁替尼的强大免疫调节作用及其与免疫检查点阻断联合治疗慢性淋巴细胞性白血病的治疗潜力。
Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment of multiple B-cell malignancies, including chronic lymphocytic leukemia (CLL). In addition to blocking B-cell receptor signaling and chemokine receptor-mediated pathways in CLL cells, that are known drivers of disease, ibrutinib also affects the microenvironment in CLL via targeting BTK in myeloid cells and IL-2–inducible T-cell kinase (ITK) in T cells. These non-BTK effects were suggested to contribute to the success of ibrutinib in CLL. By using the Eμ-TCL1 adoptive transfer mouse model of CLL, we observed that ibrutinib effectively controls leukemia development, but also results in significantly lower numbers of CD8+ effector T cells, with lower expression of activation markers, as well as impaired proliferation and effector function. Using CD8+ T cells from a T-cell receptor (TCR) reporter mouse, we verified that this is due to a direct effect of ibrutinib on TCR activity, and demonstrate that co-stimulation via CD28 overcomes these effects. Most interestingly, combination of ibrutinib with blocking antibodies targeting PD-1/PD-L1 axis in vivo improved CD8+ T-cell effector function and control of CLL. In summary, these data emphasize the strong immunomodulatory effects of ibrutinib and the therapeutic potential of its combination with immune checkpoint blockade in CLL.
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DOI：
10.1038/nrdp.2016.96
发表时间：
2017-01-19
期刊：
Nature reviews. Disease primers
影响因子：
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作者：
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期刊：
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影响因子：
11.4
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通讯作者：
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影响因子：
20.3
作者：
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通讯作者：
Maus, Marcela V.