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

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 is slower 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 shows stronger antileukemia effect on AML in Rag2^-/- mice than C57BL/6 mice. Intriguingly, Natural Killer (NK) cells in Rag2^-/- mice are increased in number, highly express activation markers, and show increased cytotoxicity to leukemia cells in a coculture assay. B2m depletion that triggers missing-self recognition of NK cells impairs the growth of AML cells in vivo. In contrast, NK cell depletion accelerates AML progression in Rag2^-/- mice. Interestingly, immunogenicity of AML keeps changing during tumor evolution, showing a trend that the aggressive AMLs generate through serial transplantations are susceptible to NK cell-mediated tumor suppression in Rag2^-/- mice. Thus, we show the critical role of NK cells in suppressing the development of certain subtypes of AML using Rag2^-/- mice, which lack functional lymphocytes but have hyperactive NK cells.