Complement receptor 3 (CR3) is expressed abundantly on natural killer (NK) cells; however, whether it plays roles in NK cell-dependent
tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on
tumor surveillance. Mice deficient in CR3 (CD11b-/- mice) exhibited a more activated NK phenotype and had enhanced NK-dependent
tumor killing. In a B16-luc
melanoma-induced lung
tumor growth and
metastasis model, mice deficient in CR3 had reduced
tumor growth and
metastases, compared with WT mice. In addition, adaptive transfer of NK cells lacking CR3 (into NK-deficient mice) mediated more efficient suppression of
tumor growth and
metastases, compared with the transfer of CR3 sufficient NK cells, suggesting that CR3 can impair
tumor surveillance through suppression of NK cell function. In vitro analyses showed that engagement of CR3 with
iC3b (classical CR3
ligand) on NK cells negatively regulated NK cell activity and effector functions (i.e. direct
tumor cell killing, antibody-dependent NK-mediated
tumor killing). Cell signaling analyses showed that
iC3b stimulation caused activation of Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1) and JNK, and suppression of ERK in NK cells, supporting that
iC3b mediates negative regulation of NK cell function through its effects on SHIP-1, JNK, and ERK signal transduction pathways. Thus, our findings demonstrate a previously unknown role for CR3 in dysregulation of NK-dependent
tumor surveillance and suggest that the
iC3b/CR3 signaling is a critical negative regulator of NK cell function and may represent a new target for preserving NK cell function in
cancer patients and improving NK cell-based
therapy.