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

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. EdwardsJun 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

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Pages (from-to)	648-664.e8
Journal	Cell Stem Cell
Volume	30
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2023.04.005
State	Published - May 4 2023

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

ASJC Scopus subject areas

Genetics
Molecular Medicine
Cell Biology

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10.1016/j.stem.2023.04.005

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Hao, X., Shen, Y., Chen, N., Zhang, W., Valverde, E., Wu, L., Chan, H. L., Xu, Z., Yu, L., Gao, Y., Bado, I., Michie, L. N., Rivas, C. H., Dominguez, L. B., Aguirre, S., Pingel, B. C., Wu, Y. H., Liu, F., Ding, Y., ... Zhang, X. H. F. (2023). Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal. Cell Stem Cell, 30(5), 648-664.e8. https://doi.org/10.1016/j.stem.2023.04.005

Hao, X, Shen, Y, Chen, N, Zhang, W, Valverde, E, Wu, L, Chan, HL, Xu, Z, Yu, L, Gao, Y, Bado, I, Michie, LN, Rivas, CH, Dominguez, LB, Aguirre, S, Pingel, BC, Wu, YH, Liu, F, Ding, Y, Edwards, DG, Liu, J, Alexander, A, Ueno, NT, Hsueh, PR, Tu, CY, Liu, LC, Chen, SH, Hung, MC, Lim, B & Zhang, XHF 2023, 'Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal', Cell Stem Cell, vol. 30, no. 5, pp. 648-664.e8. https://doi.org/10.1016/j.stem.2023.04.005

@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 = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = may,

day = "4",

doi = "10.1016/j.stem.2023.04.005",

language = "English (US)",

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T1 - Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal

AU - Hao, Xiaoxin

AU - Shen, Yichao

AU - Chen, Nan

AU - Zhang, Weijie

AU - Valverde, Elizabeth

AU - Wu, Ling

AU - Chan, Hilda L.

AU - Xu, Zhan

AU - Yu, Liqun

AU - Gao, Yang

AU - Bado, Igor

AU - Michie, Laura Natalee

AU - Rivas, Charlotte Helena

AU - Dominguez, Luis Becerra

AU - Aguirre, Sergio

AU - Pingel, Bradley C.

AU - Wu, Yi Hsuan

AU - Liu, Fengshuo

AU - Ding, Yunfeng

AU - Edwards, David G.

AU - Liu, Jun

AU - Alexander, Angela

AU - Ueno, Naoto T.

AU - Hsueh, Po Ren

AU - Tu, Chih Yen

AU - Liu, Liang Chih

AU - Chen, Shu Hsia

AU - Hung, Mien Chie

AU - Lim, Bora

AU - Zhang, Xiang H.F.

PY - 2023/5/4

Y1 - 2023/5/4

N2 - 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.

AB - 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.

KW - bone marrow niches

KW - cancer

KW - hematopoiesis

KW - hematopoietic stem/progenitor cells

KW - immunotherapies

KW - MDSCs

KW - myelopoiesis

KW - osteoprogenitor

KW - scRNA-seq

KW - systemic immunosuppression

KW - High-Temperature Requirement A Serine Peptidase 1/pharmacology

KW - Neoplasms/pathology

KW - Humans

KW - Matrix Metalloproteinase 13/pharmacology

KW - Immunosuppression Therapy

KW - Ecosystem

KW - Myelopoiesis

KW - Hematopoietic Stem Cells

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DO - 10.1016/j.stem.2023.04.005

M3 - Article

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AN - SCOPUS:85153795670

SN - 1934-5909

VL - 30

SP - 648-664.e8

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 5

ER -

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

Abstract

Keywords

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