Macrophages (M/) have been reported to downmodulate the cytotoxicity of natural killer (NK) cell against solid tumor cells. However, the collaborative role between NK cells and M/ remains underappreciated, especially in hematological cancers, such as chronic myeloid leukemia (CML). We observed a higher ratio of innate immune cells (M/ and NK) to adaptive immune cells (T and B cells) in CML bone marrow aspirates, prompting us to investigate the roles of NK and M/ in CML. Using coculture models simulating the tumor inflammatory environment, we observed that M/ protects CML from NK attack only when CML was itself mycoplasmainfected and under chronic infection-inflammation condition. We found that the M/-protective effect on CML was associated with the maintenance of CD16 level on the NK cell membrane. Although the NK membrane CD16 (mCD16) was actively shed in M/ + NK + CML trioculture, the NK mCD16 level was maintained, and this was independent of the modulation of sheddase by tissue inhibitor of metalloproteinase 1 or inhibitory cytokine transforming growth factor beta. Instead, we found that this process of NK mCD16 maintenance was conferred by M/ in a contact-dependent manner. We propose a new perspective on anti-CML strategy through abrogating M/mediated retention of NK surface CD16.
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