CD26 CAR-T cells have attenuated mitochondrial and glycolytic metabolic profiling

Area of Science:

• Immunology
• Cell Biology
• Metabolic Engineering

Background:

• Chimeric antigen receptor T (CAR-T) cells can be continuously stimulated by self-antigens shared between tumor and T cells.
• Persistent antigen exposure can lead to metabolic reprogramming, influencing CAR-T cell fate and function.
• The impact of self-antigen stimulation on CAR-T cell metabolic profiling during generation remains unclear.

Purpose of the Study:

• To investigate the metabolic characteristics of CD26 CAR-T cells, which express the CD26 self-antigen.
• To determine if self-antigen expression influences CAR-T cell metabolism and function.

Main Methods:

• Evaluated mitochondrial biogenesis (content, mtDNA copy number, regulatory genes) in CD26 and CD19 CAR-T cells.
• Assessed metabolic profiling via ATP production, mitochondrial quality, and metabolism-related gene expression.
• Analyzed CAR-T cell phenotypes using memory-related markers.

Main Results:

• CD26 CAR-T cells showed increased mitochondrial biogenesis, ATP production, and oxidative phosphorylation early in expansion.
• At later stages, CD26 CAR-T cells exhibited weakened mitochondrial biogenesis, quality, oxidative phosphorylation, and glycolytic activity.
• CD19 CAR-T cells did not display these metabolic alterations.

Conclusions:

• CD26 CAR-T cells possess a distinct metabolic profile during expansion that is detrimental to their persistence and effector functions.
• Findings offer insights for optimizing CD26 CAR-T cell metabolism for improved therapeutic outcomes.