Monocyte-macrophage polarization and recruitment pathways in the tumour microenvironment of B-cell acute lymphoblastic leukaemia
Monocyte-macrophage polarization and recruitment pathways in the tumour microenvironment of B-cell acute lymphoblastic leukaemia
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DOI：
10.1111/bjh.17330
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发表时间：
2021-03-13
影响因子：
6.5
通讯作者：
D'Amico, Giovanna
中科院分区：
文献类型：
--
作者：
Dander, Erica;Fallati, Alessandra;D'Amico, Giovanna
B细胞急性淋巴细胞白血病（B-ALL）重新编程周围的骨髓（BM）基质，以创建一个支持白血病的小生境。为了阐明免疫细胞对白血病微环境的贡献，我们研究了单核细胞/巨噬细胞区室的参与，以及B-ALL发展中的几种募集途径。免疫组织化学分析显示，与对照组相比，白血病BM活检中表达CD 68的巨噬细胞增加，主要表达M2样标记物CD 163和CD 206。此外，在B-ALL患者的外周血中，表达高水平CX 3CR 1的“非经典”CD 14（+）CD 16（++）单核细胞亚群显著增加。CX 3CL 1显示在白血病BM血浆中显著上调，从而提供可能引导NC单核细胞募集到BM中的改变的迁移途径。此外，单核细胞/巨噬细胞趋化因子配体2（CCL 2）在白血病BM血浆中强烈增加，可能是因为白血病细胞与间充质基质细胞和血管细胞的相互作用，以及白血病相关炎症介质的刺激作用。C5 a，一种巨噬细胞化学引诱物和M2极化因子，在白血病BM中进一步上调，可能是PTX 3减少的影响，这可能释放补体级联激活。总体而言，去调节的单核细胞/巨噬细胞区室是B-ALL诊断时广泛BM微环境重塑的一部分，并且可以代表与经典化疗相结合的新型治疗的有价值的靶点。
B-cell acute lymphoblastic leukaemia (B-ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia-supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B-ALL development. Immunohistochemistry analyses showed that CD68-expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2-like markers CD163 and CD206. Furthermore, the "non-classical" CD14(+)CD16(++) monocyte subset, expressing high CX3CR1 levels, was significantly increased in B-ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia-related inflammatory mediators. C5a, a macrophage chemoattractant and M2-polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B-ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy.