Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.-猫眼课题宝

DOI：

10.1016/j.ccell.2023.04.016

发表时间：

2023-05

期刊：

Cancer cell

影响因子：

50.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Chengsong Yan;Lin Zheng;Shutan Jiang;Haochen Yang;Jun Guo;Lu-yi Jiang;Tongzhou Li;Haosong Zhang;Yibing Bai;Yu Lou;Qi Zhang;T. Liang;W. Schamel;Haopeng Wang;Weiwei Yang;Guangchuan Wang;Zheng-Jiang Zhu;B. Song;Chenqi Xu

靶向胆固醇代谢来治疗癌症的概念已经在临床上得到了广泛的测试，但好处是有限的，需要对肿瘤内细胞的胆固醇代谢有一个完整的了解。我们分析了肿瘤微环境中的胆固醇图谱，发现肿瘤内T细胞胆固醇缺乏，而免疫抑制性骨髓细胞和肿瘤细胞显示胆固醇丰富。低胆固醇水平抑制T细胞增殖并引起自噬介导的凋亡，特别是对于细胞毒性T细胞。在肿瘤微环境中，氧固醇介导LXR和SREBP 2途径的相互改变，导致T细胞胆固醇缺乏，随后导致异常的代谢和信号传导途径，驱动T细胞耗竭/功能障碍。嵌合抗原受体T（CAR-T）细胞中的LXRβ耗竭导致针对实体瘤的抗肿瘤功能改善。由于T细胞胆固醇代谢和氧固醇通常与其他疾病有关，因此新的机制和胆固醇正常化策略可能在其他地方具有潜在的应用。

The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of cholesterol metabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironment and find that intratumoral T cells have cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display cholesterol abundance. Low cholesterol levels inhibit T cell proliferation and cause autophagy-mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXRβ depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since T cell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.

Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.

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