title: Human leukocyte antigen E contributes to protect tumor cells from lysis by natural killer cells.
abstract: The nonclassic class I human leukocyte antigen E (HLA-E) molecule engages the inhibitory NKG2A receptor on several cytotoxic effectors, including natural killer (NK) cells. Its tissue distribution was claimed to be wider in normal than in neoplastic tissues, and surface HLA-E was undetectable in most tumor cell lines. Herein, these issues were reinvestigated taking advantage of HLA-E-specific antibodies, immunohistochemistry, and biochemical methods detecting intracellular and surface HLA-E regardless of conformation. Contrary to published evidence, HLA-E was detected in a few normal epithelia and in a large fraction (approximately 1/3) of solid tumors, including those derived from HLA-E-negative/low-normal counterparts. Remarkably, HLA-E was detected in 30 of 30 tumor cell lines representative of major lymphoid and nonlymphoid lineages, and in 11 of 11, it was surface-expressed, although in a conformation poorly reactive with commonly used antibodies. Coexpression of HLA-E and HLA class I ligand donors was not required for surface expression but was associated with NKG2A-mediated protection from lysis by the cytotoxic cell line NKL and polyclonal NK cells from healthy donors, as demonstrated by antibody-mediated relief of protection in 10% to 20% of the tested target-effector combinations. NKG2A-mediated protection of additional targets became evident on NK effector blocking with antibodies to activating receptors (DNAM-1, natural cytotoxicity receptors, and NKG2D). Thus, initial evidence that the long-elusive HLA-E molecule is enhanced by malignant transformation and is functional in tumor cells is presented here, although its importance and precise functional role remain to be addressed in the context of a general understanding of the NK ligand-receptor network.
authors.affiliation: Laboratory of Immunology, Regina Elena Cancer Institute CRS, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lo Monaco
authors.forename: Elisa
authors.initials: E
authors.lastname: Tremante
authors.forename: Cristina
authors.initials: C
authors.lastname: Cerboni
authors.forename: Elisa
authors.initials: E
authors.lastname: Melucci
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sibilio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Nicotra
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Natali
authors.forename: Patrizio
authors.initials: P
authors.lastname: Giacomini
mesh_terms: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D000097625:HLA-E Antigens; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055607:Receptors, Natural Killer Cell; D000097625:HLA-E Antigens; D000098862:T Lineage-Specific Activation Antigen 1; C527085:KLRK1 protein, human