Clodronate Liposomes氯膦酸鹽脂質(zhì)體清除巨噬細胞骨肉瘤模型腫瘤免疫研究

中文摘要：

化療通過尚不明確的機制引發(fā)腫瘤免疫逃逸。本研究發(fā)現(xiàn)，化療顯著上調(diào)骨肉瘤組織中CD47的表達水平，且其表達水平與患者死亡率呈正相關(guān)。我們揭示了化療誘導的巨噬細胞通過分泌白細胞介素-18（IL-18），促使腫瘤細胞上調(diào)L-氨基酸轉(zhuǎn)運蛋白2（LAT2）的表達，從而顯著增強對亮氨酸和谷氨酰胺這兩種mTORC1強效激活劑的攝取。升高的亮氨酸水平與增強的谷氨酰胺分解代謝共同激活mTORC1信號通路，進而通過c-Myc介導CD47的轉(zhuǎn)錄。抑制LAT2表達或使用LAT抑制劑處理腫瘤細胞可下調(diào)CD47，同時增強巨噬細胞對腫瘤細胞的浸潤和吞噬能力，使骨肉瘤小鼠模型對阿霉素治療更為敏感。這些發(fā)現(xiàn)揭示了巨噬細胞與腫瘤細胞間的雙向調(diào)控機制在腫瘤免疫逃逸中的關(guān)鍵作用，并提示通過干預LAT2介導的氨基酸攝取通路可能為優(yōu)化癌癥治療提供新策略。

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.

論文信息：

論文題目：

Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion

期刊名稱：Nature Communications

時間期卷：13, Article number: 6308 (2022)

在線時間：2022年10月23日

DOI：doi.org/10.1038/s41467-022-34064-4

產(chǎn)品信息：

貨號：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology（靶點科技）

Clodronate Liposomes氯膦酸鹽脂質(zhì)體助力骨肉瘤模型研究，荷蘭Liposoma巨噬細胞清除劑Clodronate Liposomes見刊于Nature Communications：

氯膦酸二鈉脂質(zhì)體清除巨噬細胞助力骨肉瘤模型腫瘤免疫研究

Liposoma巨噬細胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

Macrophage depletion by clodronate liposomes

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.