近日，瑞士洛桑联邦理工学院Li Tang等研究人员合作发现，表达IL-10的CAR T细胞可抵抗功能障碍，并介导实体瘤和转移瘤的持久清除。相关论文于2024年1月2日在线发表在《自然—生物技术》杂志上。

为了应对肿瘤微环境中的T细胞功能障碍，研究人员通过工程设计使嵌合抗原受体（CAR）T细胞分泌白细胞介素-10 (IL-10)，从而对其进行新陈代谢强化。研究表明，IL-10 CAR T细胞能在肿瘤微环境中保持完整的线粒体结构和功能，并以线粒体丙酮酸载体依赖的方式增加氧化磷酸化。

IL-10的分泌促进了CAR T细胞的增殖和效应功能，从而在包括结肠癌、乳腺癌、黑色素瘤和胰腺癌在内的几种癌症类型的同基因小鼠和异种移植小鼠模型中，使已确立的实体瘤和转移性癌症完全消退。IL-10 CAR T细胞还能在淋巴器官中诱导干细胞样记忆反应，在肿瘤再次侵袭时提供持久保护。这些研究结果建立了一种可推广的方法，通过代谢装备来对抗CAR T细胞的功能障碍，从而根除实体瘤并提供持久的免疫保护。

据了解，CAR T细胞疗法在治疗多种造血恶性肿瘤方面取得了成功，但在实体瘤中却难以复制，部分原因是T细胞衰竭并最终导致功能障碍。

附：英文原文

Title: IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases

Author: Zhao, Yang, Chen, Jiangqing, Andreatta, Massimo, Feng, Bing, Xie, Yu-Qing, Wenes, Mathias, Wang, Yi, Gao, Min, Hu, Xiaomeng, Romero, Pedro, Carmona, Santiago, Sun, Jie, Guo, Yugang, Tang, Li

Issue&Volume: 2024-01-02

Abstract: The success of chimeric antigen receptor (CAR) T cell therapy in treating several hematopoietic malignancies has been difficult to replicate in solid tumors, in part because of T cell exhaustion and eventually dysfunction. To counter T cell dysfunction in the tumor microenvironment, we metabolically armored CAR T cells by engineering them to secrete interleukin-10 (IL-10). We show that IL-10 CAR T cells preserve intact mitochondrial structure and function in the tumor microenvironment and increase oxidative phosphorylation in a mitochondrial pyruvate carrier-dependent manner. IL-10 secretion promoted proliferation and effector function of CAR T cells, leading to complete regression of established solid tumors and metastatic cancers across several cancer types in syngeneic and xenograft mouse models, including colon cancer, breast cancer, melanoma and pancreatic cancer. IL-10 CAR T cells also induced stem cell-like memory responses in lymphoid organs that imparted durable protection against tumor rechallenge. Our results establish a generalizable approach to counter CAR T cell dysfunction through metabolic armoring, leading to solid tumor eradication and long-lasting immune protection.

DOI: 10.1038/s41587-023-02060-8

Source: https://www.nature.com/articles/s41587-023-02060-8