Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity

被引:513
作者
Mamessier, Emilie [1 ]
Sylvain, Aude [1 ]
Thibult, Marie-Laure [1 ]
Houvenaeghel, Gilles [2 ]
Jacquemier, Jocelyne [2 ]
Castellano, Remy [1 ]
Goncalves, Anthony [2 ]
Andre, Pascale [3 ]
Romagne, Francois [3 ]
Thibault, Gilles [4 ]
Viens, Patrice [2 ]
Birnbaum, Daniel [1 ,2 ]
Bertucci, Francois [1 ,2 ]
Moretta, Alessandro [5 ]
Olive, Daniel [1 ,2 ]
机构
[1] INSERM, UMR 891, Ctr Rech Cancerol Marseille, 27 Bd Lei Roure, F-13009 Marseille, France
[2] Inst Paoli Calmettes, Marseille, France
[3] Innate Pharma, Marseille, France
[4] Univ Tours, UMR CNRS GICC Immunopharmacogenet Anticorps Thera, Tours, France
[5] Univ Genoa, DIMES, Genoa, Italy
关键词
NATURAL-KILLER-CELLS; ACUTE MYELOID-LEUKEMIA; MHC CLASS-I; MESENCHYMAL TRANSITION; ACTIVATING RECEPTORS; TUMOR-DEVELOPMENT; LUNG-CANCER; IFN-GAMMA; TGF-BETA; T-CELLS;
D O I
10.1172/JCI45816
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 CD 16) 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-beta 1, 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.
引用
收藏
页码:3609 / 3622
页数:14
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