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

Author(s): 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;
Details: Publication Year 2024-05,Volume 629,Issue #8010,Page 201-210
Journal Title: Nature
Publication Type: Research article
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 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.
Publisher: Springer Nature
Keywords: Humans; Mice; Cell Line, Tumor; *Forkhead Box Protein O1/metabolism/genetics; *Immunotherapy, Adoptive; Mitochondria/metabolism; Phenotype; *Receptors, Chimeric Antigen/immunology/metabolism; *T-Lymphocytes/immunology/metabolism/cytology; Tumor Microenvironment/immunology; *Stem Cells/cytology/immunology/metabolism; *Neoplasms/immunology/pathology/therapy
Department(s): Laboratory Research; Clinical Haematology
Publisher's Version: https://doi.org/10.1038/s41586-024-07242-1
Open Access at Publisher's Site: https://doi.org/10.1038/s41586-024-07242-1
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-07-04 12:35:18

Last Modified: 2024-07-04 12:38:43