Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal
Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the 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 p...
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Veröffentlicht in: | Cell stem cell 2023-05, Vol.30 (5), p.648-664.e8 |
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Sprache: | eng |
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Zusammenfassung: | Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the 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 osteoprogenitor (OP) 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 the 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 the 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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•Osteoprogenitors (OPs) increase and induce GMP aggregation under remote tumor burden•Crosstalk between OPs and GMPs drives systemic accumulation of myeloid cells•HTRA1 on tumor-derived EVs upregulates MMP-13 in OPs to mediate CD41− GMP expansion•Myeloid accumulation causes immunosuppression that persists after tumor removal
Hao et al. demonstrate that remote solid tumors induce crosstalk between osteoprogenitors and CD41− granulocyte-monocyte progenitors, resulting in aberrant myelopoiesis and systemic immunosuppression. These effects are mediated by MMP-13 in osteoprogenitors, which is upregulated by tumor-derived extracellular vesicles and persists post-surgery. Targeting MMP-13 mitigates the lingering immunosuppression. |
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ISSN: | 1934-5909 1875-9777 |
DOI: | 10.1016/j.stem.2023.04.005 |