STAT5 is essential for inducing the suppressive subset and attenuate cytotoxicity of V2+T cells in acute myeloid leukemia

Under the sustained exposure to tumor microenvironment, effector lymphocytes may transform into the suppressive populations. gamma delta T cells are recognized as a crucial mediator and effector of immune surveillance and thereby a promising candidate for anti -tumor immunotherapy. Emerging clinical studies implicate that some gamma delta T subsets play an important role in promoting tumor progression. Our previous study identified an abnormal V delta 2+ T cells subset with regulatory features (Reg-V delta 2) in the patients with newly diagnosed acute myeloid leukemia (AML), and demonstrated that Reg-V delta 2 cells significantly suppressed the anti -AML effects of effector V delta 2 cells (Eff-V delta 2). The molecular mechanism underlying the subset transformation of V delta 2 cells remains unclear. Here, we found that the expression and activity of STAT5 were significantly induced in Reg-V delta 2 cells compared with EffV delta 2 cells, which was consistent with the differences found in primary V delta 2 cells between AML patients and healthy donors. In -vitro experiments further indicated that STAT5 was required for the induction of Reg-V delta 2 cells. The combined immunophenotypical and functional assays showed that blockage of STAT5 alleviated the immunosuppressive effect of Reg-V delta 2 cells on Eff-V delta 2 cells and enhanced the anti -AML capacity of V delta 2 cells from health donors and AML patients. Collectively, these results suggest that STAT5 acts as a critical regulator in the transformation of effector V delta 2 cells into a subset with immunosuppressive characteristics, providing a potential target for the improvement the efficacy of gamma delta T cells -based immunotherapy to treat AML and other hematologic malignancies.