Hirabayashi Koichi, Du Hongwei, Xu Yang, Shou Peishun, Zhou Xin, Fucá Giovanni, Landoni Elisa, Sun Chuang, Chen Yuhui, Savoldo Barbara, Dotti Gianpietro
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nat Cancer. 2021 Sep;2(9):904-918. doi: 10.1038/s43018-021-00244-2. Epub 2021 Sep 23.
Chimeric antigen receptor (CAR) T cells showed great activity in hematologic malignancies. However, heterogeneous antigen expression in tumor cells and suboptimal CAR-T cell persistence remain critical aspects to achieve clinical responses in patients with solid tumors. Here we show that CAR-T cells targeting simultaneously two tumor-associated antigens and providing transacting CD28 and 4-1BB costimulation, while sharing the sane CD3ζ-chain cause rapid antitumor effects in stress conditions, protection from tumor re-challenge and prevention of tumor escape due to low antigen density. Molecular and signaling studies indicate that T cells engineered with the proposed CAR design demonstrate sustained phosphorylation of T cell receptor-associated (TCR) signaling molecules and a molecular signature supporting CAR-T cell proliferation and long-term survival. Furthermore, metabolic profiling of CAR-T cells displayed induction of glycolysis that sustains rapid effector T cell function, but also preservation of oxidative functions, which are critical for T cell long-term persistence.
嵌合抗原受体（CAR）T细胞在血液系统恶性肿瘤中表现出强大的活性。然而，肿瘤细胞中抗原表达的异质性以及CAR-T细胞持久性欠佳仍是实体瘤患者实现临床反应的关键问题。在此我们表明，同时靶向两种肿瘤相关抗原并提供反式作用的CD28和4-1BB共刺激的CAR-T细胞，在共享相同的CD3ζ链时，在应激条件下可产生快速抗肿瘤作用，能抵御肿瘤再次攻击，并防止因低抗原密度导致的肿瘤逃逸。分子和信号研究表明，采用所提出的CAR设计改造的T细胞显示出T细胞受体相关（TCR）信号分子的持续磷酸化以及支持CAR-T细胞增殖和长期存活的分子特征。此外，CAR-T细胞的代谢谱显示糖酵解的诱导维持了快速效应T细胞功能，同时也保留了对T细胞长期持久性至关重要的氧化功能。
