小柯机器人

上海交通大学桂俊等研究人员合作发现，肿瘤分泌的FGF21通过重塑CD8⁺ T细胞的胆固醇代谢发挥免疫抑制作用。相关论文于2024年2月2日在线发表在《细胞—代谢》杂志上。

研究人员发现肿瘤分泌的成纤维细胞生长因子 21（FGF21）是一种关键的免疫抑制因子。FGF21在多种类型的肿瘤中上调，并促进肿瘤进展。肿瘤分泌的FGF21通过重塑CD8⁺ T细胞的胆固醇代谢，极大地破坏了抗肿瘤免疫。从机制上讲，FGF21可维持活化CD8⁺ T细胞中AKT-mTORC1- 脂醇调节元素结合蛋白1（SREBP1）信号轴的过度激活，从而导致胆固醇生物合成增加和T细胞衰竭。

敲除或使用中和抗体阻断FGF21可使AKT-mTORC1信号转导正常化，并减少CD8⁺ T细胞中胆固醇的过度积累，从而恢复CD8⁺ T的细胞毒功能并有力地抑制肿瘤生长。这些研究结果揭示了FGF21是一种阻碍抗肿瘤免疫的“分泌型免疫检查点”，这表明抑制FGF21可能是提高癌症免疫疗法疗效的一种有价值的策略。

研究人员表示，肿瘤采用多种策略逃避免疫。揭示肿瘤抑制抗肿瘤免疫的机制有助于开发免疫疗法。

附：英文原文

Title: Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells

Author: Cegui Hu, Wen Qiao, Xiang Li, Zhi-kun Ning, Jiang Liu, Sumiya Dalangood, Hanjun Li, Xiang Yu, Zhen Zong, Zhenke Wen, Jun Gui

Issue&Volume: 2024-02-02

Abstract: Tumors employ diverse strategies for immune evasion. Unraveling the mechanisms bywhich tumors suppress anti-tumor immunity facilitates the development of immunotherapies.Here, we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as a pivotalimmune suppressor. FGF21 is upregulated in multiple types of tumors and promotes tumorprogression. Tumor-secreted FGF21 significantly disrupts anti-tumor immunity by rewiringcholesterol metabolism of CD8+T cells. Mechanistically, FGF21 sustains the hyperactivation of AKT-mTORC1-sterolregulatory-element-binding protein 1 (SREBP1) signal axis in the activated CD8+T cells, resulting in the augment of cholesterol biosynthesis and T cell exhaustion.FGF21 knockdown or blockade using a neutralizing antibody normalizes AKT-mTORC1 signalingand reduces excessive cholesterol accumulation in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings reveal FGF21as a “secreted immune checkpoint” that hampers anti-tumor immunity, suggesting thatinhibiting FGF21 could be a valuable strategy to enhance the cancer immunotherapyefficacy.

DOI: 10.1016/j.cmet.2024.01.005

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00006-8

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