近日，澳大利亚墨尔本大学Phillip K. Darcy等研究人员合作发现，FOXO1可增强CAR T细胞的干性、代谢适应性和功效。这一研究成果于2024年4月10日在线发表在国际学术期刊《自然》上。

研究人员表示，嵌合抗原受体（CAR）T细胞疗法改变了急性淋巴细胞白血病、B细胞淋巴瘤和多发性骨髓瘤等血液系统恶性肿瘤的治疗方法，但CAR T细胞疗法在实体瘤中的疗效有限。这是由多种因素造成的，包括肿瘤微环境的免疫抑制作用，这种环境会导致T细胞存活率低、代谢功能障碍。对临床上使用的抗CD19 CAR T细胞的分析表明，积极的治疗效果与“干细胞样”表型和线粒体质量增加有关。

因此，研究人员试图找出能增强CAR T细胞适应性和对实体瘤疗效的转录因子。研究人员发现过表达FOXO1能促进来自健康人捐献者或患者的CAR T细胞的干细胞样表型，这与线粒体适应性、持久性和体内疗效的改善相关。因此，这项工作揭示了一种基因工程方法，可从遗传学上强化有利的代谢表型，具有很大的转化潜力，可提高CAR T细胞对实体瘤的疗效。

附：英文原文

Title: FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy

Author: Chan, Jack D., Scheffler, Christina M., Munoz, Isabelle, Sek, Kevin, Lee, Joel N., Huang, Yu-Kuan, Yap, Kah Min, Saw, Nicole Y. L., Li, Jasmine, Chen, Amanda X. Y., Chan, Cheok Weng, Derrick, Emily B., Todd, Kirsten L., Tong, Junming, Dunbar, Phoebe A., Li, Jiawen, Hoang, Thang X., de Menezes, Maria N., Petley, Emma V., Kim, Joelle S., Nguyen, Dat, Leung, Patrick S. K., So, Joan, Deguit, Christian, Zhu, Joe, House, Imran G., Kats, Lev M., Scott, Andrew M., Solomon, Benjamin J., Harrison, Simon J., Oliaro, Jane, Parish, Ian A., Quinn, Kylie M., Neeson, Paul J., Slaney, Clare Y., Lai, Junyun, Beavis, Paul A., Darcy, Phillip K.

Issue&Volume: 2024-04-10

Abstract: Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1,2,3,4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. 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 mass6,7,8. 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.

DOI: 10.1038/s41586-024-07242-1

Source: https://www.nature.com/articles/s41586-024-07242-1