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 Edwards; Jun 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

doi:10.1016/j.stem.2023.04.005

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.

Authors

Xiaoxin Hao¹, Yichao Shen², Nan Chen³, Weijie Zhang⁴, Elizabeth Valverde⁴, Ling Wu⁴, Hilda L Chan⁵, Zhan Xu⁴, Liqun Yu⁴, Yang Gao⁴, Igor Bado⁴, Laura Natalee Michie⁴, Charlotte Helena Rivas⁶, Luis Becerra Dominguez⁷, Sergio Aguirre⁸, Bradley C Pingel⁷, Yi-Hsuan Wu⁶, Fengshuo Liu⁶, Yunfeng Ding⁴, David G Edwards⁴, Jun Liu⁴, Angela Alexander⁹, Naoto T Ueno¹⁰, Po-Ren Hsueh¹¹, Chih-Yen Tu¹², Liang-Chih Liu¹³, Shu-Hsia Chen¹⁴, Mien-Chie Hung¹⁵, Bora Lim⁴, Xiang H-F Zhang¹⁶

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: xiangz@bcm.edu.

PMID: 37146584
PMCID: PMC10165729 (available on 2024-05-04)
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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Ecosystem*
Hematopoietic Stem Cells
High-Temperature Requirement A Serine Peptidase 1 / pharmacology
Humans
Immunosuppression Therapy
Matrix Metalloproteinase 13 / pharmacology
Myelopoiesis
Neoplasms* / pathology

Substances

Matrix Metalloproteinase 13
HTRA1 protein, human
High-Temperature Requirement A Serine Peptidase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding