Osteoprogenitor-GMP Crosstalk Underpins Solid Tumor-Induced Systemic Immunosuppression and Persists After Tumor Removal

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

Publication Date

5-4-2023

Journal

Cell Stem Cell

DOI

10.1016/j.stem.2023.04.005

PMID

37146584

PMCID

PMC10165729

PubMedCentral® Posted Date

5-4-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

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

Abstract

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting 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 osteoprogenitors (OPs) 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 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 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.