Macrophage protects mycoplasma‐infected chronic myeloid leukaemia cells from NK cell killing

Macrophages (Mvarphi) have been reported to downmodulate the cytotoxicity of natural killer (NK) cell against solid tumor cells. However, the collaborative role between NK cells and Mvarphi remains underappreciated, especially in hematological cancers, such as chronic myeloid leukemia (CML). We observed a higher ratio of innate immune cells (Mvarphi and NK) to adaptive immune cells (T and B cells) in CML bone marrow aspirates, prompting us to investigate the roles of NK and Mvarphi in CML. Using coculture models simulating the tumor inflammatory environment, we observed that Mvarphi protects CML from NK attack only when CML was itself mycoplasma-infected and under chronic infection-inflammation condition. We found that the Mvarphi-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 Mvarphi + 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 Mvarphi in a contact-dependent manner. We propose a new perspective on anti-CML strategy through abrogating Mvarphi-mediated retention of NK surface CD16.