School of Life Sciences, Jiangsu University, Zhenjiang, China.
Institute of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Cancer Biother Radiopharm. 2023 Sep;38(7):431-444. doi: 10.1089/cbr.2023.0022. Epub 2023 Jul 11.
4-1BB (CD137, TNFRSF9) is a type I transmembrane protein which binds its natural ligand, 4-1BBL. This interaction has been exploited to improve cancer immunotherapy. With ligand binding by 4-1BB, the nuclear factor-kappa B signaling pathway is activated, which results in transcription of corresponding genes such as interleukin-2 and interferon-γ, as well as the induction of T cell proliferation and antiapoptotic signals. Moreover, monoclonal antibodies that target-4-1BB, for example, Urelumab and Utomilumab, are widely used in the treatments of B cell non-Hodgkin lymphoma, lung cancer, breast cancer, soft tissue sarcoma, and other solid tumors. Furthermore, 4-1BB as a costimulatory domain, for chimeric antigen receptor T (CAR-T) cells, improves T cell proliferation and survival as well as reduces T cell exhaustion. As such, a deeper understanding of 4-1BB will contribute to improvements in cancer immunotherapy. This review provides a comprehensive analysis of current 4-1BB studies, with a focus on the use of targeting-4-1BB antibodies and 4-1BB activation domains in CAR-T cells for the treatment of cancer.
4-1BB（CD137，TNFRSF9）是一种 I 型跨膜蛋白，可与天然配体 4-1BBL 结合。这种相互作用已被用于改善癌症免疫疗法。通过 4-1BB 与配体结合，核因子-κB 信号通路被激活，导致相应基因（如白细胞介素-2 和干扰素-γ）的转录，以及 T 细胞增殖和抗凋亡信号的诱导。此外，靶向 4-1BB 的单克隆抗体，例如 Urelumab 和 Utomilumab，广泛用于治疗 B 细胞非霍奇金淋巴瘤、肺癌、乳腺癌、软组织肉瘤和其他实体瘤。此外，4-1BB 作为共刺激结构域，用于嵌合抗原受体 T（CAR-T）细胞，可提高 T 细胞的增殖和存活，并减少 T 细胞耗竭。因此，更深入地了解 4-1BB 将有助于改善癌症免疫疗法。本综述对当前 4-1BB 的研究进行了全面分析，重点介绍了靶向 4-1BB 抗体和 4-1BB 激活结构域在 CAR-T 细胞治疗癌症中的应用。
