FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Peter Maccallum Cancer Center; Peter Maccallum Cancer Center; University of Melbourne; Royal Melbourne Institute of Technology (RMIT); La Trobe University; Olivia Newton-John Cancer Research Institute; La Trobe University; University of Melbourne; Peter Maccallum Cancer Center; Melbourne Health; Royal Melbourne Hospital; Monash University; Monash University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6979
• DOI: 10.1038/s41586-024-07242-1
• 发表日期: 2024-05-02
• 页码: 201-210
• 关键词: differential expression analysis; antitumor-activity; ifn-gamma; memory; exhaustion; database; immunotherapy; maintenance; infection; release

摘要

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 1-4 , but the efficacy of CAR T cell therapy in solid tumours has been limited 5 . 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 6-8 . 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. Increased effectiveness of anti-cancer chimeric antigen receptor T cell therapy is associated with a stem-like phenotype through increased expression of FOXO1.