@article{b4ed4c26c447435988ea03e58eaea380,
title = "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.",
keywords = "bone marrow niches, cancer, hematopoiesis, hematopoietic stem/progenitor cells, immunotherapies, MDSCs, myelopoiesis, osteoprogenitor, scRNA-seq, systemic immunosuppression, High-Temperature Requirement A Serine Peptidase 1/pharmacology, Neoplasms/pathology, Humans, Matrix Metalloproteinase 13/pharmacology, Immunosuppression Therapy, Ecosystem, Myelopoiesis, Hematopoietic Stem Cells",
author = "Xiaoxin Hao and Yichao Shen and Nan Chen and Weijie Zhang and Elizabeth Valverde and Ling Wu and Chan, {Hilda L.} and Zhan Xu and Liqun Yu and Yang Gao and Igor Bado and Michie, {Laura Natalee} and Rivas, {Charlotte Helena} and Dominguez, {Luis Becerra} and Sergio Aguirre and Pingel, {Bradley C.} and Wu, {Yi Hsuan} and Fengshuo Liu and Yunfeng Ding and Edwards, {David G.} and Jun Liu and Angela Alexander and Ueno, {Naoto T.} and Hsueh, {Po Ren} and Tu, {Chih Yen} and Liu, {Liang Chih} and Chen, {Shu Hsia} and Hung, {Mien Chie} and Bora Lim and Zhang, {Xiang H.F.}",
note = "Funding Information: X.H.-F.Z. is supported by the US Department of Defense DAMD W81XWH-16-1-0073 (Era of Hope Scholarship), NCI CA183878 , NCI CA251950 , NCI CA221946 , NCI CA227904 , NCI CA253533 , DAMD W81XWH-20-1-0375 , Breast Cancer Research Foundation , and McNair Medical Institute . The scRNA-seq was performed at the Single Cell Genomics Core at BCM partially supported by NIH shared instrument grants ( S10OD023469 and S10OD025240 ), P30EY002520 , and CPRIT grant RP200504 . The flow cytometry analysis in this work was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT- RP180672 ), the NIH ( CA125123 and RR024574 ), and the assistance of Joel M. Sederstrom. The confocal imaging was supported by the Optical Imaging & Vital Microscopy (OiVM) core at BCM. We appreciate the blood samples of TNBC-PDX models provided by Lacey E. Dobrolecki from BCM PDX-AIM Core. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = may,
day = "4",
doi = "10.1016/j.stem.2023.04.005",
language = "English (US)",
volume = "30",
pages = "648--664.e8",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",
}