Natural killer (NK) cells recognize the absence of self MHC class I as a way to discriminate normal cells from cells in distress. In humans, this "missing self" recognition is ensured by inhibitory receptors such as KIR, which dampen NK cell activation upon interaction with their MHC class I ligands. We show here that NK cells lacking inhibitory KIR for self MHC class I molecules are present in human peripheral blood. These cells harbor a mature NK cell phenotype but are hyporesponsive to various stimuli, including MHC class I-deficient target cells. This response is in contrast to NK cells that express a single inhibitory KIR specific for self MHC class I, which are functionally competent when exposed to the same stimuli. These results show the involvement of KIR-MHC class I interactions in the calibration of NK cell effector capacities, suggesting its role in the subsequent "missing self" recognition.

NK cells are a major component of the antitumor immune response and are involved in controlling tumor progression and metastases in animal models. Here, we show that dysfunction of these cells accompanies human breast tumor progression. We characterized human peripheral blood NK (p-NK) cells and malignant mammary tumor-infiltrating NK (Ti-NK) cells from patients with noninvasive and invasive breast cancers. NK cells isolated from the peripheral blood of healthy donors and normal breast tissue were used as controls. With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity. Importantly, Ti-NK cells had more pronounced impairment of their cytotoxic potential than p-NK cells. We also identified several stroma-derived factors, including TGF-β1, involved in tumor-induced reduction of normal NK cell function. Our data therefore show that breast tumor progression involves NK cell dysfunction and that breast tumors model their environment to evade NK cell antitumor immunity. This highlights the importance of developing future therapies able to restore NK cell cytotoxicity to limit/prevent tumor escape from antitumor immunity. IntroductionBreast cancer (BC) is the primary cause of cancer deaths in women. The main cause of this mortality is the metastatic spread to other organs (1). Metastasis occurs when tumor cells acquire invasive features (2) and the ability to escape from antitumor immunity (3, 4). Defects in antitumor immunity may also facilitate BC occurrence. Indeed, mice deficient in IFN-γ production spontaneously develop mammary tumors (5). Breast tumor cells transplanted into NOD/SCID mice (which lack adaptive immunity) form noninvasive tumors, whereas the same cells transplanted into NOD/SCID/γ-c null mice (no adaptive immunity and no NK cells) form invasive tumors that metastasize rapidly (6). This effect is strictly dependent on NK cells (7). Similarly, in a highly metastatic model, BC metastasized to the lung only after elimination of NK cells by Tregs (8).Advanced BC patients show defects in antitumor immunity, such as alterations of DC maturation (9) and an increase in Treg infiltrates (10). Major impairment of peripheral blood NK cell maturation and cytotoxic functions has also been reported in metastatic BC (11). Several gene expression profiling studies have shown that a better outcome is associated with a strong cytotoxic infiltrate containing NK cells (12)(13)(14)(15). These data suggest that BC progression is linked to antitumor immunity efficiency and particularly to NK cells. However, the precise relationships between NK cells and BC progression in humans have not been studied so far.

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