肿瘤细胞治疗研究
英文原题：Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity.
Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity.
我们的研究凸显了选择性肌苷补充在增强 CAR T 疗法抗实体瘤疗效方面的潜力。
嵌合抗原受体（CAR）T 细胞治疗实体瘤受到免疫抑制性肿瘤微环境和 T 细胞持久性不足的阻碍。现有策略尚未解决微环境中的营养竞争问题。为此，本研究提出一种代谢补给方法，以肌苷作为替代燃料。研究工程化改造 CAR-T 细胞，使其表达膜结合型 CD26 和胞质腺苷脱氨酶 1（ADA1），从而将腺苷转化为肌苷。CD3/CD26 刺激后，ADA1 自分泌可激活 CAR-T 细胞，提高其迁移能力并增强其抵抗转化生长因子-β1 抑制的能力。将 ADA1 与抗 CD3 scFv 融合，可进一步提高肌苷生成并减少肿瘤细胞对其的利用。在肝细胞癌和非小细胞肺癌小鼠模型中，经代谢补给的 CAR-T 细胞比未改造 CAR-T 更能降低肿瘤负荷。总体而言，本研究显示选择性肌苷补给有望提高 CAR-T 治疗实体瘤的疗效。
Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor 1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor cell feeding. In mouse models of hepatocellular carcinoma and non-small cell lung cancer, metabolically refueled CAR T cells exhibit superior tumor reduction compared to unmodified CAR T cells. Overall, our study highlights the potential of selective inosine refueling to enhance CAR T therapy efficacy against solid tumors.
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