Hyperactive NK cells in Rag2 knockout mice inhibit the development of acute myeloid leukemia

Abstract Immunotherapy has attracted considerable attention as a therapeutic strategy for cancers including acute myeloid leukemia (AML). In this study, we found that the development of several aggressive subtypes of AML was retarded in Rag2-/- mice despite the lack of B and T lymphocytes, even compared to the immunologically normal C57BL/6 mice. Furthermore, an orally active p53-activating drug showed stronger antileukemia effect on AML in Rag2-/- mice than C57BL/6 mice. Intriguingly, NK cells in Rag2-/- mice were increased in number, highly expressed activation markers, and showed increased cytotoxicity to leukemia cells in a coculture assay. B2m depletion that triggers missing-self recognition of NK cells impaired the growth of AML cells in vivo. In contrast, NK cell depletion accelerated AML progression in Rag2-/- mice. We also found that immunogenicity of AML kept changing during tumor evolution, showing a trend that AMLs with strong leukemogenicity were susceptible to NK cell-mediated tumor suppression in Rag2-/- mice. Thus, our study highlighted the critical role of NK cells in suppressing the development of certain subtypes of AML, and demonstrated that Rag2-/- mice, which are generally considered as “immunodeficient” due to the lack of functional lymphocytes, in fact have hyperactive NK cells with the enhanced antileukemia immunity.