Overexpression of FOXO1 enhances CAR T cell polyfunctionality, metabolic fitness and efficacy against solid tumors

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.