BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells.

Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and 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 butyrophilin BTN3A1 inhibits tumor-reactive αβ T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific 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 may present a treatment strategy for tumors resistant to existing immunotherapies. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Kyle K Payne, Jessica A Mine, Subir Biswas, Ricardo A Chaurio, Alfredo Perales-Puchalt, Carmen M Anadon, Tara Lee Costich, Carly M Harro, Jennifer Walrath, Qianqian Ming, Evgenii Tcyganov, Andrea L Buras, Kristen E Rigolizzo, Gunjan Mandal, Jason Lajoie, Michael Ophir, Julia Tchou, Douglas Marchion, Vincent C Luca, Piotr Bobrowicz, Brooke McLaughlin, Ugur Eskiocak, Michael Schmidt, Juan R Cubillos-Ruiz, Paulo C Rodriguez, Dmitry I Gabrilovich, Jose R Conejo-Garcia. BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells. Science (New York, N.Y.). 2020 Aug 21;369(6506):942-949

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PMID: 32820120

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