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

Hao, XiaoxinXiaoxinHaoShen, YichaoYichaoShenChen, NanNanChenZhang, WeijieWeijieZhangValverde, ElizabethElizabethValverdeWu, LingLingWuChan, Hilda LHilda LChanXu, ZhanZhanXuYu, LiqunLiqunYuGao, YangYangGaoBado, IgorIgorBadoMichie, Laura NataleeLaura NataleeMichieRivas, Charlotte HelenaCharlotte HelenaRivasDominguez, Luis BecerraLuis BecerraDominguezAguirre, SergioSergioAguirrePingel, Bradley CBradley CPingelWu, Yi-HsuanYi-HsuanWuLiu, FengshuoFengshuoLiuDing, YunfengYunfengDingEdwards, David GDavid GEdwardsLiu, JunJunLiuAlexander, AngelaAngelaAlexanderUeno, Naoto TNaoto TUenoPO-REN HSUEHTu, Chih-YenChih-YenTuLiu, Liang-ChihLiang-ChihLiuChen, Shu-HsiaShu-HsiaChenHung, Mien-ChieMien-ChieHungLim, BoraBoraLimZhang, Xiang H-FXiang H-FZhang2023-05-192023-05-192023-05-0419345909https://scholars.lib.ntu.edu.tw/handle/123456789/631194Remote 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.enMDSCs; bone marrow niches; cancer; hematopoiesis; hematopoietic stem/progenitor cells; immunotherapies; myelopoiesis; osteoprogenitor; scRNA-seq; systemic immunosuppressionOsteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removaljournal article10.1016/j.stem.2023.04.005371465842-s2.0-85153795670https://api.elsevier.com/content/abstract/scopus_id/85153795670