肿瘤细胞治疗研究
英文原题：FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy.
FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy.
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FLASH 放疗因在正常组织中潜在更低的毒性而有望用于治疗实体瘤，但其对肿瘤免疫的治疗效应在很大程度上仍不清楚。我们利用髓母细胞瘤的基因工程小鼠模型表明，FLASH 辐射可刺激肿瘤巨噬细胞的促炎极化。单细胞转录组分析显示，FLASH 质子束辐射使巨噬细胞偏向促炎表型，并增加 T 细胞浸润。
此外，FLASH 辐射降低过氧化物酶体增殖物激活受体（PPAR）和精氨酸酶 1 的表达，并在刺激诱导条件下抑制免疫抑制性巨噬细胞极化。在机制上，FLASH 辐射消除脂质氧化酶表达和氧化低密度脂质生成，从而降低 PPAR 活性，而标准辐射则在巨噬细胞中诱导活性氧依赖性的 PPAR 激活。
值得注意的是，FLASH 放疗改善嵌合抗原受体（CAR）T 细胞的浸润和激活，并使髓母细胞瘤对 GD2 CAR-T 细胞治疗敏感。
因此，FLASH 放疗重编程巨噬细胞脂质代谢，从而逆转肿瘤免疫抑制。FLASH-CAR 联合放射免疫治疗可能为实体瘤治疗提供令人振奋的机会。
FLASH radiotherapy holds promise for treating solid tumors given the potential lower toxicity in normal tissues but its therapeutic effects on tumor immunity remain largely unknown. Using a genetically engineered mouse model of medulloblastoma, we show that FLASH radiation stimulates proinflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages toward proinflammatory phenotypes and increases T cell infiltration.
Furthermore, FLASH radiation reduces peroxisome proliferator-activated receptor- (PPAR ) and arginase 1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions.
Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low-density lipid generation to reduce PPAR activity, while standard radiation induces reactive oxygen species-dependent PPAR activation in macrophages.
Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes medulloblastoma to GD2 CAR-T cell therapy.
Thus, FLASH radiotherapy reprograms macrophage lipid metabolism to reverse tumor immunosuppression. Combination FLASH-CAR radioimmunotherapy may offer exciting opportunities for solid tumor treatment.
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