Rag2 基因敲除小鼠中过度活跃的 NK 细胞抑制急性髓系白血病的发生

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.