An intrinsic sensor of oncogenic transformation induces signal for innate immunosurveillance

Most complex metazoans face the risk of developing cancer during their lifespan. Multiple cell-autonomous mechanisms evolved to resist oncogenic transformation, including a variety of tumor suppressor pathways that control cell proliferation and apoptosis. In vertebrates, additional mechanisms of tumor resistance could potentially rely on cancer cell elimination by specialized cytotoxic leukocytes, such as natural killer (NK) cells. Such mechanisms would require that cancer cells be reliably distinguished from normal cells. The ligands for NKG2D, an activating NK cell receptor, are expressed on many tumor cell lines and at least some primary human tumors. However it is unknown whether their expression is induced as a direct result of oncogenic transformation in vivo, or if it is acquired as an indirect consequence of transformation, such as cellular stress. Here we show that NKG2D ligands are induced on spontaneously arising tumors in a mouse model of lymphomagenesis and that their expression renders tumor cells susceptible to NK-mediated killing. Importantly, expression of NKG2D ligands is induced at a distinct and early stage of tumorigenesis upon acquisition of genetic lesions unique to cancer cells. Expression of NKG2D ligands thus defines a novel, critical stage in carcinogenesis. Our data demonstrate that a combination of dysregulated activity of a dominant oncogene product (c-Myc) and haploinsufficiency of a major tumor suppressor protein (either Arf or p53), leads to this expression. These results provide genetic evidence for an intrinsic sensor of oncogenic transformation that triggers signals for innate immunosurveillance.