作者
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 Li,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
摘要
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.