Abstract 1340: The zinc finger 7 motif of TNFAIP3/A20 enforces a critical block in exhausted CD8 T cell degranulation and represents a potent target for enhancing adoptive cellular therapies for cancer.

Key Points

• The study aims to identify the regulatory mechanisms underlying CD8 T cell exhaustion and enhance their cytotoxic capabilities through targeting specific motifs.
• Conducted a genome-wide CRISPR knockout screen in stimulated human T cells.
• Identified TNFAIP3/A20 as a key suppressor of T cell persistence and cytotoxicity.
• Utilized base editing and tumor models to target the zinc finger 7 motif in A20.
• Evaluated effects on cytokine production and degranulation in preclinical models.
• ZF7-edited T cells showed improved efficacy in leukemia and melanoma models.
• Increased production of IFNgamma and TNF was noted, but these cytokines were not essential for tumor control.
• Identified an obstruction in perforin and granzyme degranulation that was relieved by ZF7 disruption.
• Found RIPK3 to play a crucial role in orchestrating degranulation in ZF7-deficient CD8 T cells.