1. BTN2A1, an immune checkpoint targeting Vγ9Vδ2 T cell cytotoxicity against malignant cells
- Author
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Carla E. Cano, Christine Pasero, Aude De Gassart, Clement Kerneur, Mélanie Gabriac, Marie Fullana, Emilie Granarolo, René Hoet, Emmanuel Scotet, Chirine Rafia, Thomas Hermman, Caroline Imbert, Laurent Gorvel, Norbert Vey, Antoine Briantais, Anne Charlotte le Floch, and Daniel Olive
- Subjects
Vγ9Vδ2 T cells ,butyrophilins ,BTN2A1 ,cancer ,BTN3A ,immunotherapy ,Biology (General) ,QH301-705.5 - Abstract
Summary: The anti-tumor response of Vγ9Vδ2 T cells requires the sensing of accumulated phosphoantigens (pAgs) bound intracellularly to butyrophilin 3A1 (BTN3A1). In this study, we show that butyrophilin 2A1 (BTN2A1) is required for BTN3A-mediated Vγ9Vδ2 T cell cytotoxicity against cancer cells, and that expression of the BTN2A1/BTN3A1 complex is sufficient to trigger Vγ9Vδ2 TCR activation. Also, BTN2A1 interacts with all isoforms of BTN3A (BTN3A1, BTN3A2, BTN3A3), which appears to be a rate-limiting factor to BTN2A1 export to the plasma membrane. BTN2A1/BTN3A1 interaction is enhanced by pAgs and, strikingly, B30.2 domains of both proteins are required for pAg responsiveness. BTN2A1 expression in cancer cells correlates with bisphosphonate-induced Vγ9Vδ2 T cell cytotoxicity. Vγ9Vδ2 T cell killing of cancer cells is modulated by anti-BTN2A1 monoclonal antibodies (mAbs), whose action relies on the inhibition of BTN2A1 binding to the Vγ9Vδ2TCR. This demonstrates the potential of BTN2A1 as a therapeutic target and adds to the emerging butyrophilin-family cooperation pathway in γδ T cell activation.
- Published
- 2021
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