A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection

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Science  03 Apr 2015:
Vol. 348, Issue 6230, pp. 136-139
DOI: 10.1126/science.1258867

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Immune cells, including natural killer (NK) cells, recognize transformed cells and eliminate them in a process termed immunosurveillance. It is thought that tumor cells evade immunosurveillance by shedding membrane ligands that bind to the NKG2D-activating receptor on NK cells and/or T cells, and desensitize these cells. In contrast, we show that in mice, a shed form of MULT1, a high-affinity NKG2D ligand, causes NK cell activation and tumor rejection. Recombinant soluble MULT1 stimulated tumor rejection in mice. Soluble MULT1 functions, at least in part, by competitively reversing a global desensitization of NK cells imposed by engagement of membrane NKG2D ligands on tumor-associated cells, such as myeloid cells. The results overturn conventional wisdom that soluble ligands are always inhibitory and suggest a new approach for cancer immunotherapy.

Natural born killers for tumors

Cancer immunotherapies work by activating cytotoxic lymphocytes, usually CD8+ T cells, to kill tumors. But adding new approaches to the arsenal might boost these therapies. Deng et al. now report that natural killer (NK) cells, another type of lymphocyte, can also kill tumors (see the Perspective by Steinle and Cerwenka). Mouse tumors secrete a protein called MULT1 that binds to a protein called NKG2D on the surface of NK cells. This activates NK cells and signals them to kill the tumor cells. Treating tumorbearing mice with soluble MULT1 caused their NK cells to reject the tumors.

Science, this issue p. 136; see also p. 45

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