Tumor-derived CSF-1 induces the NKG2D ligand RAE-1δ on tumor-infiltrating macrophages.

NKG2D is an important immunoreceptor expressed on the surface of NK cells and some T cells. NKG2D recognizes a set of ligands typically expressed on infected or transformed cells, but recent studies have also documented NKG2D ligands on subsets of host non-tumor cells in tumor-bearing animals and humans. Here we show that in transplanted tumors and genetically engineered mouse cancer models, tumor-associated macrophages are induced to express the NKG2D ligand RAE-1 delta. We find that a soluble factor produced by tumor cells is responsible for macrophage RAE-1 delta induction, and we identify tumor-derived colony-stimulating factor-1 (CSF-1) as necessary and sufficient for macrophage RAE-1 delta induction in vitro and in vivo. Furthermore, we show that induction of RAE-1 delta on macrophages by CSF-1 requires PI3K p110 alpha kinase signaling. Thus, production of CSF-1 by tumor cells leading to activation of PI3K p110 alpha represents a novel cellular and molecular pathway mediating NKG2D ligand expression on tumor-associated macrophages.