Identification of the immunosuppressive effect of gamma delta T cells correlated to bone morphogenetic protein 2 in acute myeloid leukemia

Description of immune landscapes in malignant microenvironment is critical to the improvement of therapeutic strategies for various tumors. Acute myeloid leukemia (AML) remains a severe life-threatening malignancy and often confronts treatment dilemma in clinic. Although gamma delta T cells exhibit independent and potent cytotoxicity against leukemic cells in vitro and in the mouse models, efficacy of gamma delta T cell-based immunotherapy on AML patients has seemed unsatisfying so far. How the anti-AML capacity of gamma delta T cells is suppressed in vivo remains elusive. Herein, we found an aberrant gamma delta T cells subset expressing CD25(+)CD127(low)V delta 2(+) in the bone marrows of patients with newly diagnosed AML. The emergence of this subset was significantly associated with disease status and risk stratification as well as with the abnormally increased bone morphogenetic protein 2 (BMP2). Mechanistically, BMP2 could directly induce CD25(+)CD127(low)V delta 2(+) gamma delta T cells (named as Reg-V delta 2) in vitro. The immunosuppressive features of Reg-V delta 2 cells were identified by combining immunophenotypical and functional data. Furthermore, inhibition of BMP2 pathway significantly blocked the emergence of Reg-V delta 2 cells and enhanced the anti-AML immunity in humanized mice. These findings not only provide a novel insight into the mechanisms of immunosuppression in the context of leukemia, but also suggest potential targets for the treatment of AML and other hematopoietic malignancies.