逃避(道德)
免疫系统
生物
CD47型
代谢控制分析
新陈代谢
氨基酸
化学
细胞生物学
免疫学
生物化学
生物技术
胰岛素
作者
Zenan Wang,Binghao Li,Shan Li,Wenlong Lin,Zhan Wang,Shengdong Wang,Weida Chen,Shi Wei,Tao Chen,Hao Zhou,Eloy Yinwang,Wenkan Zhang,Haochen Mou,Xupeng Chai,Jiahao Zhang,Zhimin Lu,Zhaoming Ye
标识
DOI:10.1038/s41467-022-34064-4
摘要
Abstract Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.
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