The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-or tumor necrosis factor–related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1 and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.

NKG2D is a key homodimeric activation receptor expressed on the cell surface of almost all NK cells, cells, some cytolytic CD8 T cells and NKT cells, and a small subset of CD4 T cells (1–5). Several ligands that bind to NKG2D are members of the MHC class Ib family (5, 6). In humans, the polymorphic MHC class I chain–related molecules (MIC) A and MICB can be recognized by NKG2D (3, 7). Although MIC molecules have not been found in mice, the retinoic acid