Shed Natural Killer Cell Ligands Can Be Activating

Natural killer (NK) cells are innate immune cells that play a key role in cancer immunosurveillance by recognizing and eliminating tumor cells. One way tumor cells may evade NK cells is through excreting or shedding ligands of NKG2D, an activating receptor on the surface of NK cells. Although the function of soluble NKG2D ligands is not entirely clear, they are thought to downregulate NKG2D expression on NK cell surfaces by promoting receptor endocytosis and to induce defects in NK cell activation due to persistent engagement and resulting desensitization of NKG2D. Deng and colleagues transduced murine tumor cells that normally do not shed NKG2D ligands with the NKG2D ligand MULT1 and made the unexpected observation that these tumor cells were rejected by syngeneic mice in an NK cell–dependent manner. Tumor cells engineered to release MULT1 or injection of recombinant MULT1 into tumors stimulated NK functional activity, suggesting that soluble MULT1 induces tumor rejection by activating NK cells. However, unlike membrane-bound MULT1, which crosslinks and activates NKG2D while simultaneously downregulating its expression on the cell surface, soluble MULT1 did not directly activate NKG2D and did upregulate its cell surface expression. This observation led the authors to hypothesize that other NKG2D ligands expressed on non-tumor host cell membranes persistently engage NKG2D on NK cells, leading to NKG2D downmodulation and NK cell desensitization, whereas soluble MULT1 blocks these interactions to increase NK cell responsiveness. Indeed, tumor-associated myeloid cells displayed NKG2D ligands such as RAE-1 that downregulated NKG2D cell surface expression on NK cells and suppressed functional NK responses to tumor cells, whereas recombinant MULT1 blocked the binding of RAE-1 to NKG2D. In addition to establishing that soluble NK cell ligands are not always inhibitory, these findings raise the possibility that activating soluble ligands could be used to augment antitumor immune responses.

Deng W, Gowen BG, Zhang L, Wang L, Lau S, Iannello A, et al. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 2015 Mar 5 [Epub ahead of print].

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