2. Academic Validation
  3. Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal

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

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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