Alexander E Doan, Katherine P Mueller, Andy Y Chen, Geoffrey T Rouin, Yingshi Chen, Bence Daniel, John Lattin, Martina Markovska, Brett Mozarsky, Jose Arias-Umana, Robert Hapke, In-Young Jung, Alice Wang, Peng Xu, Dorota Klysz, Gabrielle Zuern, Malek Bashti, Patrick J Quinn, Zhuang Miao, Katalin Sandor, Wenxi Zhang, Gregory M Chen, Faith Ryu, Meghan Logun, Junior Hall, Kai Tan, Stephan A Grupp, Susan E McClory, Caleb A Lareau, Joseph A Fraietta, Elena Sotillo, Ansuman T Satpathy, Crystal L Mackall, Evan W Weber
A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1 . The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6 , suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells...
April 10, 2024: Nature