Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Laboratory of Cancer Pathobiology and Therapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
Nat Commun. 2024 Sep 12;15(1):7662. doi: 10.1038/s41467-024-51873-x.
Most patients with advanced cancer develop cachexia, a multifactorial syndrome characterized by progressive skeletal muscle wasting. Despite its catastrophic impact on survival, the critical mediators responsible for cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in the advanced cancer milieu and promotes skeletal muscle loss. Unbiased transcriptome analysis reveals that interleukin 36 gamma (IL36G)-producing CD38 CiMs are induced in chronic monocytic blood cancer characterized by prominent cachexia. Notably, the emergence of CiMs and the activation of CiM-related gene signatures in monocytes are confirmed in various advanced solid cancers. Stimuli of toll-like receptor 4 signaling are responsible for the induction of CiMs. Genetic inhibition of IL36G-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer models. These findings indicate that the IL36G-producing subset of neutrophil-like monocytes could be a potential therapeutic target in cancer cachexia.
大多数晚期癌症患者都会出现恶病质，这是一种多因素综合征，其特征是进行性骨骼肌消耗。尽管恶病质对生存有灾难性影响，但导致恶病质发展的确切介质仍未明确界定。在这里，我们发现晚期癌症环境中会出现一种独特的类中性粒细胞样单核细胞亚群，我们称之为恶病质诱导性单核细胞（CiM），并促进骨骼肌丢失。无偏倚转录组分析显示，在以明显恶病质为特征的慢性单核细胞血液癌中，会诱导产生白细胞介素 36γ（IL36G）的 CD38 CiM。值得注意的是，CiM 的出现以及 CiM 相关基因特征在单核细胞中的激活在各种晚期实体瘤中得到了证实。Toll 样受体 4 信号的刺激是 CiM 诱导的原因。遗传抑制 IL36G 介导的信号转导可减轻骨骼肌丢失，并挽救晚期癌症模型中的恶病质表型。这些发现表明，产生 IL36G 的类中性粒细胞样单核细胞亚群可能是癌症恶病质的一个潜在治疗靶点。
