Deletion of CD38 enhances CD19 chimeric antigen receptor T cell function

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• Cell surface molecules on activated T-cells can inhibit T-cell function, acting as immune checkpoints.
• CD38 is upregulated on activated T-cells, but its precise inhibitory role and mechanism remain unclear.
• Existing immune checkpoint inhibitors like PD1, CTLA4, LAG3, and TIM3 have been studied for improving engineered immune cell function.

Purpose of the Study:

• To investigate the role of CD38 in T-cell function and its potential as an immune checkpoint.
• To evaluate the impact of CD38 deletion on the function of chimeric antigen receptor (CAR) T-cells.
• To elucidate the mechanism by which CD38 exerts its inhibitory effects on T-cells.

Main Methods:

• Comparison of CD38 expression levels with other known immune checkpoint molecules (PD1, CTLA4, LAG3, TIM3) on activated T-cells.
• Deletion of CD38 from human CAR T-cells and assessment of their in vitro exhaustion resistance and in vivo anti-tumor activity.
• Reintroduction of CD38 mutants into CD38-deficient T-cells to study its enzymatic activities and metabolite production.

Main Results:

• CD38 exhibits more sustained and intense expression on activated T-cells compared to PD1, CTLA4, LAG3, and TIM3.
• CD38 deletion in CAR T-cells resulted in relative resistance to exhaustion in vitro and enhanced anti-tumor function in vivo.
• CD38 was found to be crucial for producing immunosuppressive adenosine and utilizing nicotinamide adenine dinucleotide (NAD) in T-cells.

Conclusions:

• CD38 functions as an immunometabolic checkpoint in T-cells.
• CD38 deletion represents a potential strategy for enhancing the efficacy of CAR T-cell therapy.
• Understanding CD38's role in adenosine production and NAD utilization provides insights into T-cell regulation.