美国纽约威尔康奈尔医院Juan R. Cubillos-Ruiz小组近日取得一项新成果。他们报道了Transgelin 2保护T细胞脂质代谢和抗肿瘤功能。相关论文于2024年10月23日发表于国际顶尖学术期刊《自然》杂志上。

研究团队报告细胞骨架组织者transgelin2（TAGLN2）在CD8+ T细胞中，对于脂肪酸摄取、线粒体呼吸和抗癌功能是必需的。TAGLN2与脂肪酸结合蛋白质5（FABP5）相互作用，促进其在活化的CD8⁺ T细胞中的细胞表面定位和功能。对卵巢癌标本的分析表明，肿瘤微环境诱导的内质网（ER）应激反应抑制了TAGLN2浸润CD8⁺ T细胞，从而强化了它们的功能失调状态。

恢复内质网应激CD8⁺ T中，TAGLN2的表达细胞的脂质摄取、线粒体呼吸和细胞毒能力增加。因此嵌合抗原受体T过表达TAGLN2的细胞绕过肿瘤诱导的内质网应激的有害影响，并在转移性卵巢癌小鼠中显示出治疗效果。他们的研究确立了细胞骨架蛋白TAGLN2在T细胞脂质代谢中的作用，并强调通过维持TAGLN2–FABP5轴来增强实体恶性肿瘤中的细胞免疫治疗的潜力。

据了解，增强对病原体和肿瘤的有效免疫依赖于T细胞外脂肪酸。脂肪酸结合蛋质5（FABP5）在这一过程中发挥关键作用，协调脂质的有效输入和运输，为线粒体呼吸提供燃料，以维持CD8⁺ T细胞的生物能量需求。然而，控制这一免疫代谢轴的机制仍未被探索。

附：英文原文

Title: Transgelin 2 guards T cell lipid metabolism and antitumour function

Author: Hwang, Sung-Min, Awasthi, Deepika, Jeong, Jieun, Sandoval, Tito A., Chae, Chang-Suk, Ramos, Yusibeska, Tan, Chen, Marin Falco, Matas, Salvagno, Camilla, Emmanuelli, Alexander, McBain, Ian T., Mishra, Bikash, Ivashkiv, Lionel B., Zamarin, Dmitriy, Cantillo, Evelyn, Chapman-Davis, Eloise, Holcomb, Kevin, Morales, Diana K., Yu, Xiaoqing, Rodriguez, Paulo C., Conejo-Garcia, Jose R., Kaczocha, Martin, Vhrautio, Anna, Song, Minkyung, Cubillos-Ruiz, Juan R.

Issue&Volume: 2024-10-23

Abstract: Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of Tcells by extracellular fatty acids1,2,3. Fatty-acid-binding protein5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ Tcells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ Tcells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ Tcells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ Tcells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ Tcells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor Tcells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in Tcell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2–FABP5 axis.

DOI: 10.1038/s41586-024-08071-y

Source: https://www.nature.com/articles/s41586-024-08071-y