{Reference Type}: Journal Article
{Title}: Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal.
{Author}: 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 XH;
{Journal}: Cell Stem Cell
{Volume}: 30
{Issue}: 5
{Year}: 2023 05 4
{Factor}: 25.269
{DOI}: 10.1016/j.stem.2023.04.005
{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.