{"id":"doi:10.1038/s41586-022-05126-w","kind":"article","title":"RASA2 ablation in T cells boosts antigen sensitivity and long-term function","authors":["Julia C. Carnevale","Eric Shifrut","Nupura Kale","William A. Nyberg","Franziska Blaeschke","Yan Yi Chen","Zhongmei Li","Sagar P. Bapat","Morgan E. Diolaiti","Patrick C. O’Leary","Shane Vedova","Julia A. Belk","Bence Dániel","Theodore L. Roth","Stefanie Bachl","Alejandro Allo Anido","Brooke L. Prinzing","Jorge Ibañez-Vega","Shannon Lange","Dalia Haydar","Marie Luetke-Eversloh","Maëlys Born-Bony","Bindu Hegde","Scott C. Kogan","Tobias F. Feuchtinger"],"author_count":33,"year":2022,"published":"2022-08-24","venue":"Nature","cited_by":243,"doi":"10.1038/s41586-022-05126-w","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41586-022-05126-w","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41586-022-05126-w","updated":null,"pmid":"36002574","pmcid":null,"openalex_id":"W4293004820","pdf_url":"https://www.nature.com/articles/s41586-022-05126-w.pdf","abstract":"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 antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["CAR-T cell therapy research"],"details":null,"provenance":"openalex","attribution":"Abstract of \"RASA2 ablation in T cells boosts antigen sensitivity and long-term function\" by Julia C. Carnevale, Eric Shifrut, Nupura Kale et al., https://doi.org/10.1038/s41586-022-05126-w, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-editing-therapies","name":"CRISPR & Gene-Editing Therapies","domain_slug":"medicine"}],"cited_in_dossiers":[]}