IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing anti-tumor efficacy
Castelli, S.; Wilson, W. V.; Uslu, U.; Finck, A.; Assenmacher, C.-A.; Atoche, S. J.; Siurala, M.; Young, R. M.; June, C. H.
Show abstract
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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Pooled screening for CAR function identifies novel IL13Rα2-targeted CARs for treatment of glioblastoma 97%
- Combined PARP14 Inhibition and PD-1 Blockade Promotes Cytotoxic T Cell Quiescence and Modulates Macrophage Polarisation in Relapsed Melanoma 97%
- Tumor-Specific CD8+ T Cells from the Bone Marrow Resist Exhaustion and Exhibit Increased Persistence in Tumor-Bearing Hosts as Compared to Tumor Infiltrating Lymphocytes 96%
Similar papers in this journal
- Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell fate decisions by neoantigen-specific CD8+ T cells 97%
- IL-3-driven T cell-basophil crosstalk enhances anti-tumor immunity 96%
- Microenvironmental correlates of immune checkpoint inhibitor response in human melanoma brain metastases revealed by T cell receptor and single-cell RNA sequencing 96%
Similar papers in this journal
- Neoantigen Cancer Vaccines and Different Immune Checkpoint Therapies Each Utilize Both Converging and Distinct Mechanisms that in Combination Enable Synergistic Therapeutic Efficacy 97%
- Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells 96%
- A Human Tumor-Immune Organoid Model of Glioblastoma 96%
Similar papers in this journal
- Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor resistant HER2-positive breast cancer 97%
- TGF--dependent Lymphoid Tissue Residency of Stem-like T cells Limits the Response to Tumor Vaccine 97%
- Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors 96%
Similar papers in this journal
- Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2 96%
- Pinpointing the tumor-specific T-cells via TCR clusters 95%
- Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.