PDF(Pubmed)
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.
摘要：
远程肿瘤破坏骨髓（BM）生态系统（BME），引起BM来源的免疫抑制细胞的过量生产。然而,潜在的机制仍然知之甚少。在这里，我们表征了乳腺癌和肺癌诱导的BME在肿瘤切除前后的变化。远程肿瘤逐渐导致骨原（OP）扩张，造血干细胞脱位,和CD41-粒细胞-单核细胞祖细胞(GMP)聚集。肿瘤夹带的BME的特征在于CD41-GMPs和OP之间的共定位。OP消融消除了这种作用，并减少了异常的骨髓过度生产。机械上,由肿瘤衍生的小细胞外囊泡携带的HTRA1上调OPs中的MMP-13，这反过来又诱导了造血程序的改变。重要的是,这些作用在术后持续存在,并继续损害抗肿瘤免疫力.MMP-13的条件性敲除或抑制加速免疫恢复并恢复免疫疗法的功效。因此,肿瘤诱导的全身效应是由OP-GMP串扰引发的，其持续时间超过肿瘤负荷，并且需要额外的治疗来逆转这些效果以获得最佳的治疗效果。
