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

Julia Carnevale (), Eric Shifrut (), Nupura Kale, William A. Nyberg, Franziska Blaeschke, Yan Yi Chen, Zhongmei Li, Sagar P. Bapat, Morgan E. Diolaiti, Patrick O’Leary, Shane Vedova, Julia Belk, Bence Daniel, Theodore L. Roth, Stefanie Bachl, Alejandro Allo Anido, Brooke Prinzing, Jorge Ibañez-Vega, Shannon Lange, Dalia Haydar, Marie Luetke-Eversloh, Maelys Born-Bony, Bindu Hegde, Scott Kogan, Tobias Feuchtinger, Hideho Okada, Ansuman T. Satpathy, Kevin Shannon, Stephen Gottschalk, Justin Eyquem (), Giedre Krenciute (), Alan Ashworth () and Alexander Marson ()
Additional contact information
Julia Carnevale: Gladstone–UCSF Institute of Genomic Immunology
Eric Shifrut: Gladstone–UCSF Institute of Genomic Immunology
Nupura Kale: University of California, San Francisco
William A. Nyberg: Gladstone–UCSF Institute of Genomic Immunology
Franziska Blaeschke: Gladstone–UCSF Institute of Genomic Immunology
Yan Yi Chen: Gladstone–UCSF Institute of Genomic Immunology
Zhongmei Li: Gladstone–UCSF Institute of Genomic Immunology
Sagar P. Bapat: University of California San Francisco
Morgan E. Diolaiti: University of California, San Francisco
Patrick O’Leary: University of California, San Francisco
Shane Vedova: Gladstone–UCSF Institute of Genomic Immunology
Julia Belk: Stanford University
Bence Daniel: Stanford University
Theodore L. Roth: Stanford University
Stefanie Bachl: Gladstone–UCSF Institute of Genomic Immunology
Alejandro Allo Anido: St Jude Children’s Research Hospital
Brooke Prinzing: St Jude Children’s Research Hospital
Jorge Ibañez-Vega: St Jude Children’s Research Hospital
Shannon Lange: St Jude Children’s Research Hospital
Dalia Haydar: St Jude Children’s Research Hospital
Marie Luetke-Eversloh: St Jude Children’s Research Hospital
Maelys Born-Bony: St Jude Children’s Research Hospital
Bindu Hegde: University of California, San Francisco
Scott Kogan: University of California, San Francisco
Tobias Feuchtinger: Dr von Hauner Children’s Hospital, University Hospital, LMU
Hideho Okada: University of California, San Francisco
Ansuman T. Satpathy: Gladstone–UCSF Institute of Genomic Immunology
Kevin Shannon: University of California, San Francisco
Stephen Gottschalk: St Jude Children’s Research Hospital
Justin Eyquem: Gladstone–UCSF Institute of Genomic Immunology
Giedre Krenciute: St Jude Children’s Research Hospital
Alan Ashworth: University of California, San Francisco
Alexander Marson: Gladstone–UCSF Institute of Genomic Immunology

Nature, 2022, vol. 609, issue 7925, 174-182

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 checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3–10. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05126-w

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