Wang Haoran, Guo Hao, Yang Jingyi, Liu Yanyan, Liu Xingchen, Zhang Qing, Zhou Keshu
Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Jinshui District, Zhengzhou, 450003, China.
Exp Hematol Oncol. 2022 Sep 22;11(1):60. doi: 10.1186/s40164-022-00315-9.
Targeting B-cell receptor signalling using Bruton tyrosine kinase (BTK) inhibitors (BTKis) has become a highly successful treatment modality for B-cell malignancies, especially for chronic lymphocytic leukaemia. However, long-term administration of BTKis can be complicated by adverse on- and/or off-target effects in particular cell types. BTK is widely expressed in cells of haematopoietic origin, which are pivotal components of the tumour microenvironment. BTKis, thus, show broad immunomodulatory effects on various non-B immune cell subsets by inhibiting specific immune receptors, including T-cell receptor and Toll-like receptors. Furthermore, due to the off-target inhibition of other kinases, such as IL-2-inducible T-cell kinase, epidermal growth factor receptor, and the TEC and SRC family kinases, BTKis have additional distinct effects on T cells, natural killer cells, platelets, cardiomyocytes, and other cell types. Such mechanisms of action might contribute to the exceptionally high clinical efficacy as well as the unique profiles of adverse effects, including infections, bleeding, and atrial fibrillation, observed during BTKi administration. However, the immune defects and related infections caused by BTKis have not received sufficient attention in clinical studies till date. The broad involvement of BTK in immunological pathways provides a rationale to combine BTKis with specific immunotherapies, such as immune checkpoint inhibitor or chimeric antigen receptor-T-cell therapy, for the treatment of relapsed or refractory diseases. This review discusses and summarises the above-mentioned issues as a reference for clinicians and researchers.
使用布鲁顿酪氨酸激酶（BTK）抑制剂（BTKis）靶向B细胞受体信号通路已成为治疗B细胞恶性肿瘤，尤其是慢性淋巴细胞白血病的一种非常成功的治疗方式。然而，长期使用BTKis可能会因特定细胞类型中的不良靶向和/或脱靶效应而变得复杂。BTK在造血来源的细胞中广泛表达，而造血来源的细胞是肿瘤微环境的关键组成部分。因此，BTKis通过抑制包括T细胞受体和Toll样受体在内的特定免疫受体，对各种非B免疫细胞亚群表现出广泛的免疫调节作用。此外，由于对其他激酶的脱靶抑制，如白细胞介素-2诱导型T细胞激酶、表皮生长因子受体以及TEC和SRC家族激酶，BTKis对T细胞、自然杀伤细胞、血小板、心肌细胞和其他细胞类型具有额外的独特作用。这些作用机制可能有助于BTKis在临床应用中表现出极高的疗效以及独特的不良反应谱，包括感染、出血和心房颤动。然而，迄今为止，BTKis引起的免疫缺陷和相关感染在临床研究中尚未得到足够的关注。BTK在免疫途径中的广泛参与为将BTKis与特定免疫疗法，如免疫检查点抑制剂或嵌合抗原受体T细胞疗法联合用于治疗复发或难治性疾病提供了理论依据。本综述讨论并总结上述问题，为临床医生和研究人员提供参考。
