PT  - JOURNAL ARTICLE
AU  - Castelli, Sofía
AU  - Wilson, Wesley V.
AU  - Uslu, Ugur
AU  - Finck, Amanda
AU  - Assenmacher, Charles-Antoine
AU  - Atoche, Sebastian J.
AU  - Siurala, Mikko
AU  - Young, Regina M.
AU  - June, Carl H.
TI  - IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing anti-tumor efficacy
AID  - 10.1101/2025.01.30.635582
DP  - 2025 Jan 01
TA  - bioRxiv
PG  - 2025.01.30.635582
4099  - http://biorxiv.org/content/early/2025/02/04/2025.01.30.635582.short
4100  - http://biorxiv.org/content/early/2025/02/04/2025.01.30.635582.full
AB  - The success of chimeric antigen receptor T cell therapies targeting solid tumors is limited by the immunosuppressive tumor microenvironment. We demonstrate that endowing CAR T cells with ectopic interleukin-9 (IL-9) signaling by co-expressing an IL-9 receptor, rewires CAR T cell fate under antigen stress to enhance anti-tumor efficacy. In preclinical solid tumor models, IL-9-signaling CAR T cells exhibit increased expansion, persistence, and tumor infiltration, resulting in superior tumor control at significantly lower doses than conventional products. Trajectory and RNA velocity analyses of single-cell RNA sequencing data reveal that IL-9 signaling alters CAR T cell differentiation under antigen stress away from dysfunction, favoring a multipotent transition toward CD8+ cell memory and effector states, and promoting a CD4+ cell proliferative state. Interrogation of transcription factor pathways indicates that IL-9-mediated activation of STAT1 and STAT4 drives the superior phenotype of IL-9-signaling CAR T cells, providing a promising therapeutic strategy for targeting solid cancers.Competing Interest StatementR.M.Y. and S.C. are inventors on patent(s) and/or patent application(s) licensed to Kite Pharma and Novartis Institutes of Biomedical Research and receive license revenue from such licenses. C.H.J. is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research, Kite Pharma, Capstan Therapeutics, Dispatch Biotherapeutics and BlueWhale Bio. C.H.J. is a member of the scientific advisory boards of AC Immune, BluesphereBio, BlueWhale Bio, Cabaletta, Carisma, Cartography, Cellares, Celldex, Decheng, Poseida, Replay Bio, Verismo, and WIRB-Copernicus. M.S. is an inventor on patents and/or patent applications licensed to Kite Pharma and Dispatch Biotherapeutics.