BTN3A1 governs antitumor responses by coordinating αβ and γδ 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: United States The American Association for the Advancement of Science 21.08.2020
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - therapeutic use; Anticancer properties; Antigens, CD - genetics; Antigens, CD - immunology; Antitumor activity; B7 antigen; Butyrophilin; Butyrophilins - antagonists & inhibitors; Butyrophilins - genetics; Butyrophilins - immunology; Cancer; Cancer immunotherapy; CD45 antigen; Cell activation; Cytotoxicity; Female; Humans; Immune system; Immunotherapy; Immunotherapy - methods; Intraepithelial Lymphocytes - immunology; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mice; Mice, Transgenic; Ovarian Neoplasms - immunology; Ovarian Neoplasms - therapy; Peripheral blood; Receptor mechanisms; Receptors; Receptors, Antigen, T-Cell, alpha-beta - immunology; Restoration; T cell receptors; Toxicity; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• 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 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.