Journal
FRONTIERS IN IMMUNOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.594540
Keywords
chemotherapy; myeloid cell; monocyte; neutrophil; immunosuppression
Categories
Funding
- National Institutes of Health [1R01CA215523, 1R01CA238514, 1R03CA212829]
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The expansion of myeloid cells induced by cyclophosphamide (CTX) is an intrinsic process of hematopoietic recovery after chemotherapy. The repopulated monocytes acquire long-lasting immunosuppressive activity and gene signature characteristic of neutrophil precursors. The expansion is regulated by DNA methyltransferase 1 (Dnmt1) and dependent on chemotherapy-induced microbial translocation.
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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