The Monocytes That Repopulate in Mice After Cyclophosphamide Treatment Acquire a Neutrophil Precursor Gene Signature and Immunosuppressive Activity.
The Monocytes That Repopulate in Mice After Cyclophosphamide Treatment Acquire a Neutrophil Precursor Gene Signature and Immunosuppressive Activity.
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DOI：
10.3389/fimmu.2020.594540
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发表时间：
2020
影响因子：
7.3
通讯作者：
Zhou G
中科院分区：
文献类型：
--
作者：
Ding ZC;Aboelella NS;Bryan L;Shi H;Zhou G
环磷酰胺（CTX）是临床上用于为癌症患者进行造血干细胞移植或过继性T细胞治疗做准备的化疗预处理方案的主要组分。先前的研究表明，在小鼠和患者中以非清髓性剂量给予CTX导致骨髓细胞扩增，其中单核细胞亚群表现出免疫抑制活性。然而，这些CTX诱导的单核细胞的个体发育和基因表达特征尚未明确。在这里，我们报告说，骨髓细胞的扩增是化疗后造血恢复固有的默认过程。在这个过程中，小鼠体内重新增殖的单核细胞获得免疫抑制活性，这种活性在化疗停止后可以持续很长时间。此外，单核细胞获得中性粒细胞前体的基因特征，其特征在于增殖能力增加和多个初级和次级颗粒的表达升高。我们提供的证据表明，CTX诱导的髓系细胞扩增受DNA甲基转移酶1（Dnmt 1）的调节，并依赖于化疗诱导的微生物易位。这些发现有助于我们进一步了解化疗后髓系细胞再生的分化、异质性和功能。
Cyclophosphamide (CTX) is a major component of the chemotherapy conditioning regimens used in the clinic to prepare cancer patients for hematopoietic stem cell transplantation or adoptive T cell therapy. Previous studies have shown that CTX given at nonmyeloablative doses in mice and patients leads to expansion of myeloid cells within which the monocytic subset exhibits immunosuppressive activity. However, the ontogeny and gene expression signature of these CTX-induced monocytes are not well-defined. Here, we report that the expansion of myeloid cells is a default process intrinsic to hematopoietic recovery after chemotherapy. During this process, the monocytes repopulated in mice acquire immunosuppressive activity, which can persist long after cessation of chemotherapy. Moreover, monocytes acquire a gene signature characteristic of neutrophil precursors, marked by increased proliferative capability and elevated expressions of multiple primary and secondary granules. We provide evidence that CTX-induced myeloid cell expansion is regulated by DNA methyltransferase 1 (Dnmt1) and dependent on chemotherapy-induced microbial translocation. These findings help advance our understanding of the differentiation, heterogeneity, and function of myeloid cells repopulating after chemotherapy.
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