BTN3A1 governs anti-tumor responses by coordinating alpha-beta and gamma-delta T cells

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6506; pp. 942 - 949
• Main Authors: Payne, Kyle K., Mine, Jessica A., Biswas, Subir, Chaurio, Ricardo A., Perales-Puchalt, Alfredo, Anadon, Carmen M., Costich, Tara Lee, Harro, Carly M., Walrath, Jennifer, Ming, Qianqian, Tcyganov, Evgenii, Buras, Andrea L., Rigolizzo, Kristen E., Mandal, Gunjan, Lajoie, Jason, Ophir, Michael, Tchou, Julia, Marchion, Douglas, Luca, Vincent C., Bobrowicz, Piotr, McLaughlin, Brooke, Eskiocak, Ugur, Schmidt, Michael, Cubillos-Ruiz, Juan R., Rodriguez, Paulo C., Gabrilovich, Dmitry I., Conejo-Garcia, Jose R.
• Format: Journal Article
• Language: English
• Published: 21.08.2020
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aay2767

Gamma delta (γδ) T-cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ MHC-independent tumoricidal potential. Activation of γδ T-cells can be elicited by butyrophilin/butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members. Yet how they regulate and coordinate αβ and γδ T-cell responses remains unknown. Here, we report that the BTN3A1 butyrophilin inhibits tumor-reactive αβ TCR activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277 antibodies elicit coordinated restoration of αβ T-cell effector activity, and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1 + cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αβ and γδ T-cells, and could enable novel interventions for tumors resistant to existing immunotherapies. BTN3A1 governs anti-tumor T-cells