IL-4 drives exhaustion of CD8 + CART cells.
Carli M StewartElizabeth L SieglerR Leo SakemuraMichelle J CoxTruc N HuynhBrooke L KimballLong MaiIsmail CanClaudia Manriquez RomanKun YunOlivia SirpillaJames H GirschEkene OgbodoWazim Mohammed IsmailAlexandre Gaspar-MaiaJustin BudkaJenny KimNathalie SchollerMike MattieSimone FilostoSaad Sirop KenderianPublished in: Nature communications (2024)
Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8 + CART cells develop signs of exhaustion independently of the presence of CD4 + CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.
Keyphrases
- cell therapy
- induced apoptosis
- single cell
- cell cycle arrest
- clinical trial
- genome wide
- stem cells
- mesenchymal stem cells
- oxidative stress
- signaling pathway
- monoclonal antibody
- randomized controlled trial
- cell death
- dna methylation
- high throughput
- mouse model
- transcription factor
- study protocol
- bone marrow
- copy number
- newly diagnosed