title: Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition.
abstract: Breast cancer is the leading cause of death for women between the ages of 35 to 65. This is mostly due to intertumor heterogeneity and the lack of specific therapies for all subtypes. However, some breast cancers with an unexpected good prognosis are associated with enhanced antitumor immunity in situ. We studied whether breast cancer subtypes might have different susceptibilities to natural killer (NK) cells' antitumor immunity. We collected a large public set of microarray data for primary breast tumors and determined NK cell ligand expression. We found that despite heterogeneous levels of inhibitory HLA members, NKG2D ligands and DNAM ligands are expressed in virtually all breast tumor subtypes. Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent. In parallel, we showed that cell lines and primary breast tumor cells secrete soluble inhibitory factors that alter NK cell functions. Finally, we showed that these mechanisms of escape occur in vivo in the MMTV-Neu model of spontaneous murine breast cancer. Our study shows that breast cancer cells, independent of the subtype, have developed different mechanisms to escape from NK cells' antitumor immunity. These results emphasize the role of NK cells in breast tumor clearance and underlie the importance of devising future therapy aiming at enhancing NK cell-mediated recognition in parallel with the prevention of the tumor-editing process.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Genova, Italy. 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: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Rémy
authors.initials: R
authors.lastname: Castellano
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: Gilles
authors.initials: G
authors.lastname: Houvenaeghel
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charaffe-Jaufret
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004967:Estrogens; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007694:Killer Cells, Natural / Q000145:classification / Q000276:immunology*; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011374:Progesterone; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000276:immunology; D017634:Self Tolerance; D019139:Tumor Escape; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D004967:Estrogens; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011971:Receptors, Immunologic; D011374:Progesterone