FOXO1过表达可增强人类CAR-T对小鼠肿瘤移植模型的疗效 因此，该研究结果表明，通过基因工程方法强化细胞线粒体代谢有利表现型，产生超高水平的FOXO1，从而改善CAR-T代谢、促进CAR-T像干（gàn）细胞一样不断增殖分化并延长续航时间，提高CAR-T对抗实体肿瘤的有效性和持久性，故有必要进一步开展临床研究进行验证。 对此，英国《自然》和美国《科学》自由撰稿人发表同期评论：如何让抗癌细胞强而持久？赋予它们干（gàn）细胞技能！ Nature. 2024 Apr 10. IF: 64.8 FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy. Chan JD, Scheffler CM, Munoz I, Sek K, Lee JN, Huang YK, Yap KM, Saw NYL, Li J, Chen AXY, Chan CW, Derrick EB, Todd KL, Tong J, Dunbar PA, Li J, Hoang TX, de Menezes MN, Petley EV, Kim JS, Nguyen D, Leung PSK, So J, Deguit C, Zhu J, House IG, Kats LM, Scott AM, Solomon BJ, Harrison SJ, Oliaro J, Parish IA, Quinn KM, Neeson PJ, Slaney CY, Lai J, Beavis PA, Darcy PK. The University of Melbourne, Parkville, Victoria, Australia; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Royal Melbourne Hospital, Melbourne, Victoria, Australia; La Trobe University, Melbourne, Victoria, Australia; Royal Melbourne Institute of Technology University, Bundoora, Victoria, Australia; Monash University, Clayton, Victoria, Australia. Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma, but the efficacy of CAR T cell therapy in solid tumours has been limited. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours. PMID: 38600376 DOI: 10.1038/s41586-024-07242-1 Nature. 2024 Apr 10. IF: 64.8 How to supercharge cancer-fighting cells: give them stem cell skills. The bioengineered immune players called CAR T cells last longer and work better if pumped up with a large dose of a protein that makes them resemble stem cells. Reardon S. PMID: 38600202 DOI: 10.1038/d41586-024-01043-2 文献共享
