Chemotherapy-induced reactive myelopoiesis promotes expansion of immunosuppressive neutrophil-like monocytes in mice and humans
Huidong Shi, Zhi-Chun Ding, Ogacheko D. Okoko, Xin Wang, George Zhou, Yan Ye, Md Yeashin Gazi, Caitlin Brandle, Lirong Pei, Rafal Pacholczyk, Catherine C. Hedrick, Locke J. Bryan, Gang Zhou
Huidong Shi, Zhi-Chun Ding, Ogacheko D. Okoko, Xin Wang, George Zhou, Yan Ye, Md Yeashin Gazi, Caitlin Brandle, Lirong Pei, Rafal Pacholczyk, Catherine C. Hedrick, Locke J. Bryan, Gang Zhou
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Research Article Immunology Oncology

Chemotherapy-induced reactive myelopoiesis promotes expansion of immunosuppressive neutrophil-like monocytes in mice and humans

Abstract

Cytotoxic chemotherapy primarily targets rapidly proliferating cancer cells but also depletes normal myeloid cells. The resulting cell loss triggers reactive myelopoiesis, a compensatory process in which hematopoietic stem and progenitor cells in the bone marrow (BM) regenerate myeloid lineages. We previously showed that the alkylating agent cyclophosphamide (CTX) induces myelopoiesis, leading to the expansion of immunosuppressive monocytes in mice. However, the molecular features and clinical relevance of these cells remain poorly understood. Here, we report the emergence of immunosuppressive monocytes in the peripheral blood of lymphoma patients receiving CTX-containing chemotherapy. To gain mechanistic insight into CTX-induced myelopoiesis, we performed single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on BM monocytes from CTX-treated mice. These analyses revealed a heterogeneous monocyte population and demonstrated that CTX skews myelopoiesis toward the generation of neutrophil-like monocytes (NeuMo). Moreover, CTX-induced NeuMo cells, enriched within the CXCR4+CX3CR1– monocyte subset, exhibited potent T cell–suppressive activity. Using the NeuMo gene signature, reanalysis of public scRNA-seq datasets identified a transcriptionally similar monocyte subset in chemotherapy-treated cancer patients. Collectively, our findings suggest that the expansion of NeuMo cells following chemotherapy represents a conserved immunoregulatory feedback mechanism with potential impact on tumor response to chemoimmunotherapy.

Authors

Huidong Shi, Zhi-Chun Ding, Ogacheko D. Okoko, Xin Wang, George Zhou, Yan Ye, Md Yeashin Gazi, Caitlin Brandle, Lirong Pei, Rafal Pacholczyk, Catherine C. Hedrick, Locke J. Bryan, Gang Zhou

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Figure 1

Emergence of immunosuppressive monocytes in the PBMCs of lymphoma patients following chemotherapy.

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Emergence of immunosuppressive monocytes in the PBMCs of lymphoma patien...
(A) As depicted in the schema, patients received 6 cycles of standard-of-care chemotherapy. PBMC samples collected before chemotherapy and after 4 cycles of treatment were cryopreserved. HLA-DR–CD11b+CD14+CD33+ monocytes were FACS-sorted from pre- and post-chemotherapy PBMCs and used for in vitro T cell suppression assays. T cells isolated from a healthy donor were labeled with violet dye and used as responder cells. T cells were stimulated with Human T-Activator CD3/CD28 Dynabeads in the presence of pre- or post-chemotherapy monocytes. Cells were harvested 3 days later and evaluated for CD4+ and CD8+ T cell proliferation status by FACS. Violet dye histograms show T cell proliferation status under control cell culture conditions. The controls included T cells without stimulation (top row), T cells stimulated alone (middle row), and T cells stimulated in the presence of monocytes sorted from the PBMCs of a healthy donor (bottom row). (B) Patient samples showing that immunosuppressive monocytes were absent in pre-chemotherapy patient PBMCs but emerged in post-chemotherapy patient PBMCs. (C) Patient samples showing that immunosuppressive monocytes were present in pre-chemotherapy patient PBMCs. Post-chemotherapy monocytes from these patients showed either enhanced or reduced T cell suppression activities. Numbers in histograms represent percentage of divided T cells.