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

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