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

Area of Science:

• Immunology
• Cell Biology
• Cancer Therapy

Background:

• Chimeric antigen receptor (CAR) T cell therapies show promise but are limited by poor T cell persistence.
• T cell memory programs are crucial for sustained CAR T cell function and clinical efficacy.
• Identifying factors that regulate T cell memory and exhaustion is critical for improving CAR T cell therapy.

Purpose of the Study:

• To investigate the role of the transcription factor FOXO1 in regulating memory and exhaustion in human CAR T cells.
• To determine if FOXO1 manipulation can enhance CAR T cell function, persistence, and anti-tumor activity.
• To assess the clinical relevance of FOXO1 in CAR T cell therapy and tumor-infiltrating lymphocytes.

Main Methods:

• Pharmacological inhibition and gene editing of endogenous FOXO1 in CAR T cells.
• Overexpression of FOXO1 in CAR T cells.
• Analysis of gene expression, chromatin accessibility, and T cell phenotypes.
• In vivo studies assessing CAR T cell persistence and tumor control.
• Correlation analysis of FOXO1 activity with clinical outcomes.

Main Results:

• FOXO1 inhibition diminished memory gene expression, induced exhaustion, and impaired anti-tumor activity.
• FOXO1 overexpression promoted a T cell memory gene-expression program and increased chromatin accessibility.
• FOXO1-overexpressing CAR T cells maintained function, memory potential, and metabolic fitness under chronic stimulation.
• FOXO1 overexpression enhanced in vivo CAR T cell persistence and tumor control.
• TCF1 overexpression did not confer similar memory benefits.
• FOXO1 activity correlated with favorable clinical outcomes in patients receiving CAR T cell or TIL therapy.

Conclusions:

• FOXO1 is a key regulator of memory and exhaustion in human CAR T cells.
• Overexpression of FOXO1 enhances CAR T cell anti-tumor activity, persistence, and memory potential.
• FOXO1 represents a promising target for optimizing therapeutic T cell states in cancer immunotherapy.