Targeting BTN2A1 Enhances Vγ9Vδ2 T-Cell Effector Functions and Triggers Tumor Cell Pyroptosis
Vγ9Vδ2 T cells are potent but elusive cytotoxic effectors. Butyrophilin subfamily 2 member A1 (BTN2A1) is a surface protein that has recently been shown to bind the Vγ9 chain of the γδ T-cell receptor, but its precise role in modulating Vγ9Vδ2 T-cell functions remains unknown. Here, we show that 107G3B5, a monoclonal BTN2A1 agonist antibody, was able to significantly enhance Vγ9Vδ2 T-cell functions against hematologic or solid cell lines and against primary cells from patients with adult acute lymphoblastic leukemia. New computer vision strategies applied to holotomographic microscopy videos showed that 107G3B5 enhanced the interaction between Vγ9Vδ2 T cells and target cells in a quantitative and qualitative manner. In addition, we found that Vγ9Vδ2 T cells activated by 107G3B5 induced caspase 3/7 activation in tumor cells, thereby triggering tumor cell death by pyroptosis. Together, these data demonstrate that targeting BTN2A1 with 107G3B5 enhances the Vγ9Vδ2 T-cell antitumor response by triggering pyroptosis-induced immunogenic cell death. These new pyroptosis-based therapies have great potential to stimulate the immune system to fight cancer, especially "cold" tumors. See related Spotlight by Kabelit, p. 1662.
Authors
- Anne-Charlotte Le Floch (ORCID: https://orcid.org/0009-0007-2605-4145)
- Amandine Anastasio (ORCID: https://orcid.org/0000-0001-6101-8210)
- Caroline Imbert (ORCID: https://orcid.org/0000-0001-7946-6791)
- Nicolas Boucherit (ORCID: https://orcid.org/0000-0002-2295-2470)
- Geoffrey Guittard (ORCID: https://orcid.org/0000-0002-6061-8553)
- Lydie Crescence (ORCID: https://orcid.org/0000-0002-3468-8435)
- Mathieu Fréchin (ORCID: https://orcid.org/0000-0002-2310-5230)
- Daniel Olive (ORCID: https://orcid.org/0000-0003-1299-4113)
- Stéphane Fattori (ORCID: https://orcid.org/0000-0002-7435-9222)
- Florence Orlanducci
- Antoine Briantais (ORCID: https://orcid.org/0000-0002-0905-1731)
- Laurent Gorvel (ORCID: https://orcid.org/0000-0001-7526-261X)
- Christophe Dubois (ORCID: https://orcid.org/0000-0003-2421-6087)
- Norbert Vey (ORCID: https://orcid.org/0000-0001-7027-040X)
- Lorenzo Archetti (ORCID: https://orcid.org/0009-0007-2473-4980)
- Laurence Panicot‐Dubois (ORCID: https://orcid.org/0000-0003-0848-5009)
- Aude Le Roy (ORCID: https://orcid.org/0000-0001-8003-7142)
- Carla E. Cano
Institutions
- Centre National de la Recherche Scientifique (FR)
- Ciena (United States) (US)
- Inserm (FR)
- Aix-Marseille Université (FR)
- Institut Pprime (FR)
- Génétique et Immunologie des Maladies Parasitaires (FR)
- Délégation Provence et Corse (FR)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Centre de Recherche en Cancérologie de Marseille (FR)
- Institut Paoli-Calmettes (FR)
- Nutrition, Obésité et Risque Thrombotique (FR)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1158/2326-6066.cir-23-0868
- Citations
- 8
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.92
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Institut National Du Cancer
- Direction Générale de l’offre de Soins
- PHENOMIN