美国西奈山伊坎医学院Miriam Merad团队发现，胆固醇动员调节树突状细胞成熟及其对癌症的免疫应答。相关论文于2025年1月21日在线发表在《自然—免疫学》杂志上。

研究人员发现，常规树突状细胞（cDC）通过利用其内部的胆固醇储备（从细胞外碎片中获取或通过新生合成产生）在成熟的cDC细胞表面组装脂质纳米结构，增强成熟标志物的表达并稳定免疫受体信号传导。

该过程依赖于胆固醇通过尼曼–匹克病类型C1（NPC1）的转运，并介导稳态及Toll样受体（TLR）诱导的成熟。值得注意的是，研究人员鉴定了受体酪氨酸激酶AXL作为调控NPC1依赖性脂质纳米结构构建的因子。删除cDC中的AXL可增强其成熟，从而改善抗肿瘤免疫。

总的来说，该研究提供了胆固醇动员作为cDC成熟基本机制的新见解，并强调AXL作为调节cDC的治疗靶点。

研究人员表示，cDC的成熟对于维持抗自身免疫的耐受性保护机制以及促进对病原和癌症的免疫应答至关重要。cDC成熟的亚细胞机制仍然不完全明确。

附：英文原文

Title: Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer

Author: Belabed, Meriem, Park, Matthew D., Blouin, Cdric M., Balan, Sreekumar, Moon, Chang Y., Freed, Grace, Quijada-lamo, Miguel, Peros, Ante, Mattiuz, Raphal, Reid, Amanda M., Yatim, Nader, Boumelha, Jesse, Azimi, Camillia S., LaMarche, Nelson M., Troncoso, Leanna, Amabile, Angelo, Le Berichel, Jessica, Chen, Steven T., Wilk, C. Matthias, Brown, Brian D., Radford, Kristen J., Ghosh, Sourav, Rothlin, Carla V., Yvan-Charvet, Laurent, Marron, Thomas U., Puleston, Daniel J., Wagenblast, Elvin, Bhardwaj, Nina, Lamaze, Christophe, Merad, Miriam

Issue&Volume: 2025-01-21

Abstract: Maturation of conventional dendritic cells (cDCs) is crucial for maintaining tolerogenic safeguards against auto-immunity and for promoting immunogenic responses to pathogens and cancer. The subcellular mechanism for cDC maturation remains poorly defined. We show that cDCs mature by leveraging an internal reservoir of cholesterol (harnessed from extracellular cell debris and generated by de novo synthesis) to assemble lipid nanodomains on cell surfaces of maturing cDCs, enhance expression of maturation markers and stabilize immune receptor signaling. This process is dependent on cholesterol transport through Niemann–Pick disease type C1 (NPC1) and mediates homeostatic and Toll-like receptor (TLR)-induced maturation. Importantly, we identified the receptor tyrosine kinase AXL as a regulator of the NPC1-dependent construction of lipid nanodomains. Deleting AXL from cDCs enhances their maturation, thus improving anti-tumor immunity. Altogether, our study presents new insights into cholesterol mobilization as a fundamental basis for cDC maturation and highlights AXL as a therapeutic target for modulating cDCs.

DOI: 10.1038/s41590-024-02065-8

Source: https://www.nature.com/articles/s41590-024-02065-8