文章：

靶向B细胞受体信号在癌症中的作用：临床前和临床进展

Targeting B cell receptor signalling in cancer: preclinical and clinical advances

原文发布日期：2018-01-19

DOI: 10.1038/nrc.2017.121

类型: Review Article

开放获取: 否

要点：

1. B cell receptor (BCR) signalling is indispensable for normal B cell development and adaptive immunity. In some B cell leukaemias and lymphomas, malignant B cells utilize BCR signalling for growth and survival.
2. The mechanism of activation of BCR signalling includes continuous BCR stimulation by microbial antigens and/or autoantigens that are present in the tissue microenvironment, oncogenic mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling.
3. Bruton tyrosine kinase (BTK) inhibitors and/or PI3Kδ selective inhibitors are effective against chronic lymphocytic leukaemia (CLL), mantle cell lymphoma, follicular lymphoma, Waldenstrom macroglobulinaemia (WM) and other selective B cell malignancies. In CLL and WM, BTK inhibitors are increasingly replacing chemotherapy.
4. BTK and PI3Kδ inhibitors cause redistribution of malignant B cells from tissue sites into the peripheral blood, especially in patients with CLL. How much this redistribution, resulting in a form of programmed cell death (anoikis) as a consequence of detachment of the malignant cells from their supportive tissue microenvironment, contributes to the efficacy of these agents remains unclear. The involvement of BTK, PI3Kδ and other BCR-related kinases such as spleen tyrosine kinase (SYK) in the signalling and function of homing receptors (chemokine receptors and integrins) appears to be the molecular basis for this B cell redistribution.
5. BTK and PI3Kδ are also expressed in non-malignant cells in the microenvironment, such as T cells and monocytes and macrophages. The effects of BTK and PI3Kδ inhibitors extend to these cell lineages, which may contribute to antitumour effects but can give rise to side effects. In addition, ibrutinib, the most widely used BTK inhibitor, also targets inducible T cell kinase (ITK), a related kinase that promotes T helper 2 (T_H 2) cell differentiation.
6. B cells and macrophages are part of a tumour-supportive microenvironment in solid tumours, including pancreatic cancer. Targeting B cell and/or macrophage function yields antitumour effects in preclinical models, and this strategy is being investigated in ongoing clinical trials.

要点翻译：

1. B细胞受体（BCR）信号传导对于正常B细胞发育和适应性免疫不可或缺。在某些B细胞白血病和淋巴瘤中，恶性B细胞利用BCR信号传导促进生长与存活。
2. BCR信号传导的激活机制包括：组织微环境中微生物抗原和/或自身抗原的持续BCR刺激、BCR复合体或其下游信号元件的致癌突变，以及不依赖于配体的持续性BCR信号传导。
3. 布鲁顿酪氨酸激酶（BTK）抑制剂和/或PI3Kδ选择性抑制剂对慢性淋巴细胞白血病（CLL）、套细胞淋巴瘤、滤泡性淋巴瘤、华氏巨球蛋白血症（WM）及其他选择性B细胞恶性肿瘤具有疗效。在CLL和WM治疗中，BTK抑制剂正逐步取代化疗方案。
4. BTK与PI3Kδ抑制剂会促使恶性B细胞从组织部位重新分布至外周血，这一现象在CLL患者中尤为明显。这种重新分布导致恶性细胞脱离支持性组织微环境，引发一种程序性细胞死亡（失巢凋亡），但其对药物疗效的具体贡献程度尚不明确。BTK、PI3Kδ及其他BCR相关激酶（如脾酪氨酸激酶SYK）参与归巢受体（趋化因子受体与整合素）的信号传导和功能，构成了B细胞重新分布的分子基础。
5. BTK与PI3Kδ在微环境非恶性细胞（如T细胞、单核细胞和巨噬细胞）中同样有表达。BTK和PI3Kδ抑制剂会作用于这些细胞谱系，虽可能增强抗肿瘤效应，但也会引发副作用。此外，最广泛使用的BTK抑制剂伊布替尼还能靶向诱导性T细胞激酶（ITK），该激酶可促进辅助性T细胞2（TH2）分化。
6. 在包括胰腺癌在内的实体瘤中，B细胞和巨噬细胞构成肿瘤支持性微环境。临床前模型显示，靶向B细胞和/或巨噬细胞功能可产生抗肿瘤效应，该策略目前正在多项临床试验中进行研究。

英文摘要：

B cell receptor (BCR) signalling is crucial for normal B cell development and adaptive immunity. BCR signalling also supports the survival and growth of malignant B cells in patients with B cell leukaemias or lymphomas. The mechanism of BCR pathway activation in these diseases includes continuous BCR stimulation by microbial antigens or autoantigens present in the tissue microenvironment, activating mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling. The most established agents targeting BCR signalling are Bruton tyrosine kinase (BTK) inhibitors and PI3K isoform-specific inhibitors, and their introduction into the clinic is rapidly changing how B cell malignancies are treated. B cells and BCR-related kinases, such as BTK, also play a role in the microenvironment of solid tumours, such as squamous cell carcinoma and pancreatic cancer, and therefore targeting B cells or BCR-related kinases may have anticancer activity beyond B cell malignancies.

摘要翻译： 

B细胞受体（BCR）信号传导对正常B细胞发育和适应性免疫至关重要。BCR信号还支持B细胞白血病或淋巴瘤患者体内恶性B细胞的存活与增殖。这些疾病中BCR通路激活的机制包括：由组织微环境中存在的微生物抗原或自身抗原持续刺激BCR、BCR复合体或其下游信号组分的激活突变，以及不依赖配体的本底BCR信号。靶向BCR信号的最成熟药物为布鲁顿酪氨酸激酶（BTK）抑制剂和PI3K亚型特异性抑制剂，它们的临床应用正迅速改变B细胞恶性肿瘤的治疗方式。B细胞及BCR相关激酶（如BTK）也参与实体瘤（如鳞状细胞癌和胰腺癌）的微环境，因此靶向B细胞或BCR相关激酶可能在B细胞恶性肿瘤之外也具有抗癌活性。

原文链接：

Targeting B cell receptor signalling in cancer: preclinical and clinical advances