RASA2 ablation in T cells boosts antigen sensitivity and long-term function.

ABSTRACT: The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints^1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function^3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric anti

SUBMITTER: Carnevale J 

PROVIDER: S-EPMC9433322 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature