title: Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity.
abstract: 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.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR U891, Marseille, France. mamessier@ciml.univ-mrs.fr
authors.forename: Emilie
authors.initials: E
authors.lastname: Mamessier
authors.forename: Aude
authors.initials: A
authors.lastname: Sylvain
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Thibult
authors.forename: Gilles
authors.initials: G
authors.lastname: Houvenaeghel
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Jacquemier
authors.forename: Rémy
authors.initials: R
authors.lastname: Castellano
authors.forename: Anthony
authors.initials: A
authors.lastname: Gonçalves
authors.forename: Pascale
authors.initials: P
authors.lastname: André
authors.forename: François
authors.initials: F
authors.lastname: Romagné
authors.forename: Gilles
authors.initials: G
authors.lastname: Thibault
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D042361:Mammary Glands, Human / Q000166:cytology / Q000502:physiology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D055607:Receptors, Natural Killer Cell / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D055607:Receptors, Natural Killer Cell; D007371:Interferon-gamma