Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal

Xiaoxin Hao, Yichao Shen, Nan Chen, Weijie Zhang, Elizabeth Valverde, Ling Wu, Hilda L. Chan, Zhan Xu, Liqun Yu, Yang Gao, Igor Bado, Laura Natalee Michie, Charlotte Helena Rivas, Luis Becerra Dominguez, Sergio Aguirre, Bradley C. Pingel, Yi Hsuan Wu, Fengshuo Liu, Yunfeng Ding, David G. EdwardsJun Liu, Angela Alexander, Naoto T. Ueno, Po Ren Hsueh, Chih Yen Tu, Liang Chih Liu, Shu Hsia Chen, Mien Chie Hung, Bora Lim, Xiang H.F. Zhang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)648-664.e8
JournalCell Stem Cell
Issue number5
StatePublished - May 4 2023


  • bone marrow niches
  • cancer
  • hematopoiesis
  • hematopoietic stem/progenitor cells
  • immunotherapies
  • MDSCs
  • myelopoiesis
  • osteoprogenitor
  • scRNA-seq
  • systemic immunosuppression
  • High-Temperature Requirement A Serine Peptidase 1/pharmacology
  • Neoplasms/pathology
  • Humans
  • Matrix Metalloproteinase 13/pharmacology
  • Immunosuppression Therapy
  • Ecosystem
  • Myelopoiesis
  • Hematopoietic Stem Cells

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Cell Biology


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