中文摘要：
化疗通过尚不明确的机制引发肿瘤免疫逃逸。本研究发现，化疗显著上调骨肉瘤组织中CD47的表达水平，且其表达水平与患者死亡率呈正相关。我们揭示了化疗诱导的巨噬细胞通过分泌白细胞介素-18（IL-18），促使肿瘤细胞上调L-氨基酸转运蛋白2（LAT2）的表达，从而显著增强对亮氨酸和谷氨酰胺这两种mTORC1强效激活剂的摄取。升高的亮氨酸水平与增强的谷氨酰胺分解代谢共同激活mTORC1信号通路，进而通过c-Myc介导CD47的转录。抑制LAT2表达或使用LAT抑制剂处理肿瘤细胞可下调CD47，同时增强巨噬细胞对肿瘤细胞的浸润和吞噬能力，使骨肉瘤小鼠模型对阿霉素治疗更为敏感。这些发现揭示了巨噬细胞与肿瘤细胞间的双向调控机制在肿瘤免疫逃逸中的关键作用，并提示通过干预LAT2介导的氨基酸摄取通路可能为优化癌症治疗提供新策略。
英文摘要：
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.
论文信息：
论文题目：
Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion
期刊名称：Nature Communications
时间期卷：13, Article number: 6308 (2022)
在线时间：2022年10月23日
DOI：doi.org/10.1038/s41467-022-34064-4
产品信息：
货号：CP-005-005
规格：5ml+5ml
品牌：Liposoma
产地：荷兰
名称：Clodronate Liposomes and Control Liposomes
办事处：Target Technology（靶点科技）
Clodronate Liposomes氯膦酸盐脂质体助力骨肉瘤模型研究，荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于Nature Communications：
氯膦酸二钠脂质体清除巨噬细胞助力骨肉瘤模型肿瘤免疫研究
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：
For macrophage depletion, 200 μL clodronate liposomes (Liposoma B.V.) or PBS liposomes (Liposoma B.V.) were administered through the caudal vein 3 days prior to tumor injection and every 4 days (seven times in total). BCH was administered intravenously at 200 mg/kg per mouse the day after the first doxorubicin treatment, then every 2 days, four times. Intraperitoneal injections of CD47 mAb (Bio X cell) at a dose of 10 mg/kg was initiated the day after the first doxorubicin treatment, then every 2 days for four times. 2 × 106 SJSA-1 cells, GFP+ SJSA-1 cells, shCtrl SJSA-1 cells or shIL18R1 SJSA-1 cells were subcutaneously injected into BALB/c nude mice on day 0. Doxorubicin (5 mg/kg) was injected intraperitoneally five times every 3 days after tumor grew for 2 weeks. BCH (200 mg/kg) was injected intravenously after first doxorubicin treatment, and then every 2 days for 7 times. Clodronate liposomes were administered through the caudal vein 3 days prior to tumor injection and every 4 days for a total of nine times. Tumors were measured at indicated times and tumor volume was calculated using the formula: π/6 × length × width.
