BTN3A molecules considerably improve V9V2T cells-based immunotherapy in acute myeloid leukemia

Given their recognized ability to kill acute myeloid leukemia (AML) blasts both in vitro and in vivo, V9V2 T cells are of growing interest in the design of new strategies of immunotherapy. We show that the Butyrophilin3A (BTN3A, CD277) subfamily is a critical determinant of V9V2 TCR-mediated recognition of human primary AML blasts ex vivo. Moreover, anti-BTN3A 20.1 agonist monoclonal antibodies (mAbs) can trigger BTN3A on AML blasts leading to further enhanced V9V2 T cell-mediated killing, but this mAb had no enhancing effect upon NK cell-mediated killing. We show that monocytic differentiation of primary AML blasts accounts for their AminoBisphosphonate (N-BP)-mediated sensitization to V9V2 T cells. In addition, anti-BTN3A 20.1 mAbs could specifically sensitize resistant blasts to V9V2 T cells lysis and overcome the poor effect of N-BP treatment on those blasts. We confirmed the enhancement of V9V2 T cells activity by anti-BTN3A 20.1 mAb using a human AML xenotransplantation mouse model. We showed that anti-BTN3A 20.1 mAb combined with V9V2 T cells immunotherapy could increase animal survival and decrease the leukemic burden in blood and bone marrow. These findings could be of great interest in the design of new immunotherapeutic strategies for treating AML.