Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (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 interleukin (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.

中文翻译：

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依鲁替尼通过STAT3介导的调节性B细胞功能抑制和PD-1 / PD-L1途径抑制来调节免疫抑制性CLL微环境。

依鲁替尼是一种布鲁顿酪氨酸激酶（BTK）的共价抑制剂，已被批准用于治疗复发/难治性或未经治疗的慢性淋巴细胞性白血病（CLL）的患者。除了直接抑制BTK以外，依鲁替尼还具有靶向多种信号通路的免疫调节特性。了解依鲁替尼的这种辅助特性如何改变CLL微环境对于进一步探索该疾病的免疫反应和设计未来的联合疗法至关重要。在这里，我们研究了依鲁替尼的免疫调节特性的潜在机制。在前瞻性收集的接受依鲁替尼单药治疗的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的选择性和持久下调。进一步的分析表明，这种作用是通过抑制CLL细胞中的组成性活性信号转导子和转录激活子3（STAT3）介导的。在CD4 +和CD8 + T细胞中观察到PD-1的类似下调。我们还证实接受依鲁替尼的患者中CLL细胞的白介素（IL）-10产量降低，这也与STAT3磷酸化的抑制有关。综上所述，这些发现为依鲁替尼通过抑制STAT3途径的免疫调节提供了机械基础，STAT3途径在诱导和维持肿瘤免疫耐受中起关键作用。该数据还值得对依鲁替尼与能够增强其免疫调节作用的药物联合治疗的测试。