Details

Autor(en) / Beteiligte

• Carnevale, Julia
• Shifrut, Eric
• Kale, Nupura
• Nyberg, William A.
• Blaeschke, Franziska
• Chen, Yan Yi
• Li, Zhongmei
• Bapat, Sagar P.
• Diolaiti, Morgan E.
• O’Leary, Patrick
• Vedova, Shane
• Belk, Julia
• Daniel, Bence
• Roth, Theodore L.
• Bachl, Stefanie
• Anido, Alejandro Allo
• Prinzing, Brooke
• Ibañez-Vega, Jorge
• Lange, Shannon
• Haydar, Dalia
• Luetke-Eversloh, Marie
• Born-Bony, Maelys
• Hegde, Bindu
• Kogan, Scott
• Feuchtinger, Tobias
• Okada, Hideho
• Satpathy, Ansuman T.
• Shannon, Kevin
• Gottschalk, Stephen
• Eyquem, Justin
• Krenciute, Giedre
• Ashworth, Alan
• Marson, Alexander

Titel

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

Ist Teil von

• Nature (London), 2022-09, Vol.609 (7925), p.174-182

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Genome-wide CRISPR screens, biochemical studies and animal models show that RASA2 has a key role in regulating T cell function and has potential as a genetic target for enhancing anti-tumour immunity.