2. Academic Validation
  3. FcεRγI promotes canine CD8 chimeric antigen receptor T cell cytotoxicity through a Syk-NF-κB axis

FcεRγI promotes canine CD8 chimeric antigen receptor T cell cytotoxicity through a Syk-NF-κB axis

  • Mol Ther. 2025 Dec 10:S1525-0016(25)01033-0. doi: 10.1016/j.ymthe.2025.12.010.
Emma E Goodman 1,  Abdulla Berjis 2,  Neil C Sheppard 3,  Nicola J Mason 4,  Roddy S O'Connor 3,  Aimee S Payne 5
Affiliations

Affiliations

  • 1 Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • 2 School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • 4 Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
  • 5 Department of Dermatology, Columbia University, New York, NY 10032, USA. Electronic address: [email protected].
PMID: 41376156 DOI: 10.1016/j.ymthe.2025.12.010
Abstract

Comparative oncology has advanced Cancer Immunotherapy, although cellular mechanisms governing chimeric antigen receptor T cell (CART) therapy in canines are poorly understood. In a first-in-canine trial, anti-CD20 CART with canine 4-1BB-CD3ζ (cBBζ) domains induced CD20-negative lymphoma outgrowth but did not persist or deplete B cells. Here we show that canine CARTs incorporating human BBζ (hBBζ) demonstrate superior therapeutic function, mediated by FcεRγI. hBBζ-CART showed greater cytolysis and CD8 T cell outgrowth than cBBζ-CART in repetitive killing assays and a canine B cell leukemia xenograft model. Transcriptional profiling revealed upregulation of FCER1G and innate-like genes in CD8 hBBζ versus cBBζ-CARTs. CRISPR-mediated FCER1G deletion and pharmacologic Syk/NF-κB inhibition indicated that Syk-NF-κB signaling regulates FcεRγI-mediated enhancement of hBBζ-CART cytotoxicity, associated with increased granzyme B and IFN-γ/TNF-α production. Syk-NF-κB signaling promotes FcεRγI expression in hBBζ CARTs, and CAR-TCR interactions potentiate NF-κB signaling to upregulate FcεRγI and enhance CART function. These studies identify a potent therapeutic subset of innate-like canine CARTs induced by hBBζ signaling, which holds potential to improve both canine and human CART therapy.

Keywords

CAR-T; autoimmune disease; cancer; canine model; cell therapy; comparative oncology; immunotherapy.

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