作者
Paul A. Beavis,Phillip K. Darcy,Junyun Lai,Jack D. Chan,Kevin Sek,Christian Scheffler,Isabelle Munoz,Yen-Yu Huang,Kah Min Yap,Joel Lee,Jasmine Li,Amanda Chen,Cheok Weng Chan,Emily B. Derrick,Kirsten L. Todd,Jie Tong,Melody Menezes,Emma V. Petley,Joelle Kim,Dat Quoc Nguyen,Patrick S.C. Leung,Joan So,Christian Deo T. Deguit,Joe Jiang Zhu,Imran G. House,Lev Kats,Jane Oliaro,Ian A. Parish,Kylie M. Quinn,Paul J. Neeson,Clare Y. Slaney,Nicole Y Saw,P. Rod Dunbar,Jiawen Li,Thang Van Hoang,Benjamin Solomon,Simon J. Harrison,Andrew M. Scott
摘要
Abstract The efficacy of chimeric antigen receptor (CAR) T cell therapy is limited in solid tumors by several factors including the immunosuppressive tumor microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. To overcome this, we sought to identify transcription factors that could enhance CAR T cell fitness. We identified that the overexpression of Foxo1 could enhance the therapeutic efficacy of murine CAR T cells in the setting of syngeneic immunocompetent models and was dependent on the sustained production of proinflammatory cytokines. FOXO1 overexpression in human CAR T cells enforced broad transcriptional and epigenetic changes that led to a more “stem-like” phenotype and similarly improved therapeutic efficacy. Enhanced efficacy was associated with improved mitochondrial fitness and persistence in vivo. FOXO1 overexpression also led to a more stem like phenotype in patient derived CAR T cells and is therefore a promising strategy for the treatment of solid cancers.