CART cells are prone to Fas- and DR5-mediated cell death

Area of Science:

• Immunology
• Cell Biology
• Oncology

Background:

• Chimeric antigen receptor (CAR) T cell therapy is FDA-approved for B-cell malignancies.
• The endogenous T cell receptor (TCR) functionality in CAR T cells remains incompletely understood.
• CAR T cell persistence is critical for therapeutic efficacy.

Purpose of the Study:

• To assess the functionality of the endogenous TCR in CAR T cells.
• To investigate the mechanisms underlying CAR T cell apoptosis.
• To evaluate strategies for enhancing CAR T cell persistence.

Main Methods:

• Analysis of CAR T cell apoptosis markers (Fas, FasL, DR5, TRAIL).
• Assessment of apoptosis induction independent of antigen-mediated CAR or TCR activation.
• In vivo blockade of Fas and DR5 pathways using recombinant proteins.

Main Results:

• CAR T cells progressively upregulate Fas, FasL, DR5, and TRAIL, leading to apoptosis.
• Apoptosis occurs independently of antigen-mediated TCR or CAR activation, even with single co-stimulatory domains.
• Combined blockade of Fas and DR5 pathways significantly rescues CAR T cells in vivo.

Conclusions:

• Fas and DR5 pathways play a dominant role in CAR T cell apoptosis.
• Understanding and targeting these pathways is crucial for improving CAR T cell persistence.
• Findings support the development of novel CAR T cell applications, including combined TCR and CAR activation for solid tumors.