Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal
Journal
Cell stem cell
Journal Volume
30
Journal Issue
5
Date Issued
2023-05-04
Author(s)
Hao, Xiaoxin
Shen, Yichao
Chen, Nan
Zhang, Weijie
Valverde, Elizabeth
Wu, Ling
Chan, Hilda L
Xu, Zhan
Yu, Liqun
Gao, Yang
Bado, Igor
Michie, Laura Natalee
Rivas, Charlotte Helena
Dominguez, Luis Becerra
Aguirre, Sergio
Pingel, Bradley C
Wu, Yi-Hsuan
Liu, Fengshuo
Ding, Yunfeng
Edwards, David G
Liu, Jun
Alexander, Angela
Ueno, Naoto T
Tu, Chih-Yen
Liu, Liang-Chih
Chen, Shu-Hsia
Hung, Mien-Chie
Lim, Bora
Zhang, Xiang H-F
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.
Subjects
MDSCs; bone marrow niches; cancer; hematopoiesis; hematopoietic stem/progenitor cells; immunotherapies; myelopoiesis; osteoprogenitor; scRNA-seq; systemic immunosuppression
Type
journal article