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

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.

• Authors: 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
• Journal: Cell stem cell (Cell Stem Cell) Vol. 30 Issue 5 Pg. 648-664.e8 (05 04 2023) ISSN: 1875-9777 [Electronic] United States
• PMID: 37146584 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Matrix Metalloproteinase 13
• HtrA1 protein, human
• High-Temperature Requirement A Serine Peptidase 1

Topics

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