BTN3A1 governs antitumor responses by coordinating alpha beta and gamma delta T cells

Gamma delta (gamma delta) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of gamma delta 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 alpha beta and gamma delta T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive alpha beta T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of alpha beta T cell effector activity and BTN2A1-dependent gamma delta lymphocyte cytotoxicity against BTN3A1* cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by alpha beta and gamma delta T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.