MICA-expressing monocytes enhance natural killer cell Fc receptor-mediated antitumor functions.
Campbell AR, Duggan MC, Suarez-Kelly LP, Bhave N, Opheim KS, McMichael E, Trikha P, Parihar R, Luedke E, Lewis A, Yung B, Lee R, Raulet D, Tridandapani S, Groh V, Yu L, Yildiz V, Byrd JC, Caligiuri MA, Carson WE
Cancer Immunol Res in press 07/19/2017
Natural Killer (NK) cells are large granular lymphocytes that promote the antitumor response via communication with other cell types in the tumor microenvironment. Previously, we have shown that NK cells secrete a profile of immune stimulatory factors (e.g., IFNgamma, MIP-1alpha, TNFalpha) in response to dual stimulation with the combination of antibody (Ab)-coated tumor cells and cytokines, such as interleukin (IL) 12. We now demonstrate that this response is enhanced in the presence of autologous monocytes. Monocyte enhancement of NK cell activity was dependent on cell-to-cell contact as determined by a transwell assay. It was hypothesized that NK cell effector functions against Ab-coated tumor cells were enhanced via binding of MICA on monocytes to NK cell NKG2D receptors. Strategies to block MICA-NKG2D interactions resulted in reductions in IFNgamma production. Depletion of monocytes in vivo resulted in decreased IFNgamma production by murine NK cells upon exposure to Ab-coated tumor cells. In mice receiving trastuzumab and IL12 therapy, monocyte depletion resulted in significantly greater tumor growth in comparison to mock-depleted controls (P < 0.05). These data suggest that NK cell-monocyte interactions enhance NK cell antitumor activity in the setting of monoclonal Ab therapy for cancer.Full Text