Hyperactive Natural Killer cells in Rag2 knockout mice inhibit the development of acute myeloid leukemia
Emi Sugimoto, Jingmei Li, Yasutaka Hayashi, Kohei Iida, Shuhei Asada, Tsuyoshi Fukushima, Moe Tamura, Shiori Shikata, Wenyu Zhang, Keita Yamamoto, Kimihito C. Kawabata, Tatsuya Kawase, Takeshi Saito, Taku Yoshida, Satoshi Yamazaki, Yuta Kaito, Yoichi Imai, Tamami Denda, Yasunori Ota, Tomofusa Fukuyama, Yosuke Tanaka, Yutaka Enomoto, Toshio Kitamura, Susumu Goyama
Abstract
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 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.