FOXO1 is a master regulator of memory programming in CAR T cells

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 () and Evan W. Weber ()
Additional contact information
Alexander E. Doan: Stanford University School of Medicine
Katherine P. Mueller: University of Pennsylvania
Andy Y. Chen: Stanford University
Geoffrey T. Rouin: University of Pennsylvania
Yingshi Chen: University of Pennsylvania
Bence Daniel: Stanford University
John Lattin: Stanford University School of Medicine
Martina Markovska: University of Pennsylvania
Brett Mozarsky: University of Pennsylvania
Jose Arias-Umana: University of Pennsylvania
Robert Hapke: University of Pennsylvania
In-Young Jung: University of Pennsylvania
Alice Wang: University of Pennsylvania
Peng Xu: Stanford University School of Medicine
Dorota Klysz: Stanford University School of Medicine
Gabrielle Zuern: University of Pennsylvania
Malek Bashti: Stanford University School of Medicine
Patrick J. Quinn: Stanford University School of Medicine
Zhuang Miao: Stanford University
Katalin Sandor: Stanford University
Wenxi Zhang: Stanford University
Gregory M. Chen: University of Pennsylvania
Faith Ryu: University of Pennsylvania
Meghan Logun: University of Pennsylvania
Junior Hall: University of Pennsylvania
Kai Tan: University of Pennsylvania
Stephan A. Grupp: University of Pennsylvania
Susan E. McClory: University of Pennsylvania
Caleb A. Lareau: Stanford University
Joseph A. Fraietta: University of Pennsylvania
Elena Sotillo: Stanford University School of Medicine
Ansuman T. Satpathy: Stanford University
Crystal L. Mackall: Stanford University School of Medicine
Evan W. Weber: University of Pennsylvania

Nature, 2024, vol. 629, issue 8010, 211-218

Abstract: Abstract 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. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.

Date: 2024
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DOI: 10.1038/s41586-024-07300-8

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