NK cells are innate immune cells that help destroy NK cell–sensitive tumors, such as melanomas and gastrointestinal tumors, which express activating ligands for these cells. The activation and antitumor functions of NK cells are triggered by the binding of these ligands to the activating receptor NKG2D on the NK cells. In many cancer patients, NK cell activity is hampered by the shedding of NKG2D ligands from tumor cells or by other unknown mechanisms.

This group recently showed that a drug that activates NK cells in patients with gastrointestinal cancer improved their prognoses. They now report that the patients who did not respond to this therapy had increased numbers of circulating T reg cells, whereas the patients who responded did not. The T reg cells from nonresponding patients prevented NK cells from killing tumor cells in vitro.

In mice, transfer of T reg cells blocked the killing capacity of NK cells. This inhibition depended on the expression of membrane-bound TGF-ß on the T reg cells, which triggered the down-regulation of NKG2D on the NK cells. Thus TGF-ß–induced inhibition of NK cell activation, which normally helps curtail inflammation and prevent autoimmunity, helps certain tumors avoid being recognized by these killer cells.