Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence.
Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence.
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DOI：
10.1186/s12967-021-03136-2
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发表时间：
2021-11-22
影响因子：
7.4
通讯作者：
Ritchie DS
中科院分区：
文献类型：
--
作者：
Davis JE;Sharpe C;Mason K;Tam CS;Koldej RM;Ritchie DS
布鲁顿的酪氨酸激酶抑制剂（BTKi）治疗慢性淋巴细胞白血病（CLL）的发展提供了一个非常有效的和相对无毒的替代传统的化疗。一些研究表明，BTKi也可以导致患者T细胞免疫的改善，尽管体外分析表明BTKi对T细胞功能的免疫抑制作用。在这项研究中，我们检查了两种临床可用的BTKi，伊曲替尼和扎努替尼的体外作用和长期体内作用。对第三种BTKi（acalabrutinib）进行了额外的体外评估。对从未治疗的CLL患者和长期（> 12个月）BTKi治疗的CLL患者分离的外周血单核细胞进行免疫亚群表型分型、细胞因子分泌、T细胞脱粒和增殖测定。与之前的研究类似，我们观察到长期BTKi治疗使淋巴细胞亚群频率正常化并降低T细胞上的PD-1表达。我们还观察到，BTKi治疗前患者的T细胞显示出衰老T细胞典型的异常过度增殖模式，这通过长期BTKi治疗正常化。此外，BTKi疗法导致经历增殖的晚期世代T细胞中T细胞耗竭标志物PD-1、TIM 3和LAG3的表达降低。总的来说，这些发现表明BTKi对T细胞功能的体外作用与体内长期BTKi暴露的作用之间存在关键差异。总体长期暴露于BTKi，特别是伊曲替尼，导致T细胞适应性改善，部分原因是抑制了CLL T细胞的异常过度增殖和T细胞衰老的相关发展。在线版本包含补充材料，可通过10.1186/s12967 - 021 - 03136 - 2获得。
The development of Bruton’s tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function. In this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term (> 12 months) BTKi treatment. Similar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation. Collectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence. The online version contains supplementary material available at 10.1186/s12967-021-03136-2.
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影响因子：
10.1
作者：
Hanna BS;Yazdanparast H;Demerdash Y;Roessner PM;Schulz R;Lichter P;Stilgenbauer S;Seiffert M
通讯作者：
Seiffert M
影响因子：
11.4
作者：
Kondo K;Shaim H;Thompson PA;Burger JA;Keating M;Estrov Z;Harris D;Kim E;Ferrajoli A;Daher M;Basar R;Muftuoglu M;Imahashi N;Alsuliman A;Sobieski C;Gokdemir E;Wierda W;Jain N;Liu E;Shpall EJ;Rezvani K
通讯作者：
Rezvani K
影响因子：
20.3
作者：
Fraietta, Joseph A.;Beckwith, Kyle A.;Maus, Marcela V.
通讯作者：
Maus, Marcela V.
影响因子：
6.4
作者：
Fan, Fuli;Yoo, Hyeon Joo;Sellner, Leopold
通讯作者：
Sellner, Leopold
影响因子：
4.4
作者：
Hofland, Tom;de Weerdt, Iris;Eldering, Eric
通讯作者：
Eldering, Eric