%0 Journal Article
%T Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal.
%A Hao X
%A Shen Y
%A Chen N
%A Zhang W
%A Valverde E
%A Wu L
%A Chan HL
%A Xu Z
%A Yu L
%A Gao Y
%A Bado I
%A Michie LN
%A Rivas CH
%A Dominguez LB
%A Aguirre S
%A Pingel BC
%A Wu YH
%A Liu F
%A Ding Y
%A Edwards DG
%A Liu J
%A Alexander A
%A Ueno NT
%A Hsueh PR
%A Tu CY
%A Liu LC
%A Chen SH
%A Hung MC
%A Lim B
%A Zhang XH
%J Cell Stem Cell
%V 30
%N 5
%D 2023 05 4
%M 37146584
%F 25.269
%R 10.1016/j.stem.2023.04.005
%X 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.