Publication Date
5-4-2023
Journal
Cell Stem Cell
DOI
10.1016/j.stem.2023.04.005
PMID
37146584
PMCID
PMC10165729
PubMedCentral® Posted Date
5-4-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Humans, Matrix Metalloproteinase 13, Ecosystem, Myelopoiesis, Hematopoietic Stem Cells, Neoplasms, Immunosuppression Therapy, High-Temperature Requirement A Serine Peptidase 1
Abstract
Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitors (OPs) expansion, hematopoietic stem cell dislocation and CD41− granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41− GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in hematopoietic program. Importantly, these effects persist post-surgery and continue to impair anti-tumor immunity. Conditional knockout or inhibition of MMP-13 accelerates immune reinstatement and restores efficacies of immunotherapies. Therefore, tumor-induced systemic effects are initiated by OP-GMP crosstalk that outlasts tumor burden, and additional treatment is required to reverse these effects for optimal therapeutic efficacy.
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Biological Phenomena, Cell Phenomena, and Immunity Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Obstetrics and Gynecology Commons, Oncology Commons
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