Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway.
Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway.
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DOI：
10.1038/leu.2017.304
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Rezvani K
中科院分区：
文献类型：
--
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
伊布替尼是一种布鲁顿酪氨酸激酶（BTK）的共价抑制剂，已获批用于治疗复发性/难治性或初治性CLL患者。除了直接抑制BTK外，伊曲替尼还通过靶向多个信号通路具有免疫调节特性。了解伊曲替尼的这种辅助特性如何改变CLL微环境对于进一步探索这种疾病的免疫反应和设计未来的联合治疗至关重要。在这里，我们研究了伊鲁替尼的免疫调节特性的机制。在前瞻性采集的接受伊鲁替尼单药治疗的CLL患者的外周血样本中，我们观察到治疗后3个月CLL细胞上PD-L1的选择性和持久性下调。进一步分析表明，这种作用是通过抑制CLL细胞中组成型活性信号转导子和转录激活子3（STAT 3）介导的。在CD 4+和CD 8 + T细胞中观察到类似的PD-1下调。我们还证明了接受伊鲁替尼的患者中CLL细胞产生的IL-10减少，这也与STAT 3磷酸化的抑制有关。综上所述，这些发现为伊鲁替尼通过抑制STAT 3途径进行免疫调节提供了机制基础，这在诱导和维持肿瘤免疫耐受中至关重要。这些数据还值得测试将伊鲁替尼与能够增强其免疫调节作用的药剂组合的组合治疗。
Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve CLL. Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3-months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T-cells. We also demonstrated reduced IL-10 production by CLL cells in patients receiving ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining ibrutinib with agents capable of augmenting its immunomodulatory effects.
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影响因子：
20.3
作者：
Kim, Ekaterina;Hurtz, Christian;Burger, Jan A.
通讯作者：
Burger, Jan A.
影响因子：
20.3
作者：
Fraietta, Joseph A.;Beckwith, Kyle A.;Maus, Marcela V.
通讯作者：
Maus, Marcela V.
DOI：
10.1073/pnas.0901166106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Gorgun, Gullu;Ramsay, Alan G.;Gribben, John G.
通讯作者：
Gribben, John G.
影响因子：
15.9
作者：
Frank, DA;Mahajan, S;Ritz, J
通讯作者：
Ritz, J
影响因子：
8
作者：
Decker, T;Kovarik, P
通讯作者：
Kovarik, P