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

  • Cell Stem Cell. 2023 May 4;30(5):648-664.e8. doi: 10.1016/j.stem.2023.04.005.
Xiaoxin Hao  1 ,  Yichao Shen  2 ,  Nan Chen  3 ,  Weijie Zhang  4 ,  Elizabeth Valverde  4 ,  Ling Wu  4 ,  Hilda L Chan  5 ,  Zhan Xu  4 ,  Liqun Yu  4 ,  Yang Gao  4 ,  Igor Bado  4 ,  Laura Natalee Michie  4 ,  Charlotte Helena Rivas  6 ,  Luis Becerra Dominguez  7 ,  Sergio Aguirre  8 ,  Bradley C Pingel  7 ,  Yi-Hsuan Wu  6 ,  Fengshuo Liu  6 ,  Yunfeng Ding  4 ,  David G Edwards  4 ,  Jun Liu  4 ,  Angela Alexander  9 ,  Naoto T Ueno  10 ,  Po-Ren Hsueh  11 ,  Chih-Yen Tu  12 ,  Liang-Chih Liu  13 ,  Shu-Hsia Chen  14 ,  Mien-Chie Hung  15 ,  Bora Lim  4 ,  Xiang H-F Zhang  16
Affiliations
  • 1. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 2. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 3. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 4. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 5. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Cancer and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 7. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Immunology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 8. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 9. Department of Breast Medical Oncology and Morgan Welch IBC Research Program and Clinic, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 10. Department of Breast Medical Oncology and Morgan Welch IBC Research Program and Clinic, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; University of Hawai'i Cancer Center (UHCC), 701 Ilalo Street, Honolulu, HI 96813, USA.
  • 11. Departments of Laboratory Medicine and Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
  • 12. School of Medicine, College of Medicine, China Medical University, Taichung 406, Taiwan; Division of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
  • 13. School of Medicine, College of Medicine, China Medical University, Taichung 406, Taiwan; Division of Breast Surgery, Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
  • 14. Immunomonitoring Core, Center for Immunotherapy Research, Houston Methodist Research Institute (HMRI), Houston, TX, USA.
  • 15. Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 40402, Taiwan.
  • 16. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 37146584 DOI: 10.1016/j.stem.2023.04.005
Abstract

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.

Keywords
MDSCs; bone marrow niches; cancer; hematopoiesis; hematopoietic stem/progenitor cells; immunotherapies; myelopoiesis; osteoprogenitor; scRNA-seq; systemic immunosuppression.
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