title: Selenite induces posttranscriptional blockade of HLA-E expression and sensitizes tumor cells to CD94/NKG2A-positive NK cells.
abstract: CD94/NKG2A is an inhibitory receptor that controls the activity of a large proportion of human NK cells following interactions with the nonclassical HLA class Ib molecule HLA-E expressed on target cells. In this study, we show that selenite (SeO(3)(2-)), an inorganic selenium compound, induces an almost complete loss of cell surface expression of HLA-E on tumor cells of various origins. Selenite abrogated the HLA-E expression at a posttranscriptional level, since selenite exposure led to a dose-dependent decrease in cellular HLA-E protein expression whereas the mRNA levels remained intact. The loss of HLA-E expression following selenite treatment was associated with decreased levels of intracellular free thiols in the tumor cells, suggesting that the reduced HLA-E protein synthesis was caused by oxidative stress. Indeed, HLA-E expression and the level of free thiols remained intact following treatment with selenomethionine, a selenium compound that does not generate oxidative stress. Loss of HLA-E expression, but not of total HLA class I expression, on tumor cells resulted in increased susceptibility to CD94/NK group 2A-positive NK cells. Our results suggest that selenite may be used to potentiate the anti-tumor cytotoxicity in settings of NK cell-based immunotherapies.
authors: Department of Medicine, Center for Infectious Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
authors: Monika
authors: M
authors: Enqvist
authors: Gustav
authors: G
authors: Nilsonne
authors: Oscar
authors: O
authors: Hammarfjord
authors: Robert P A
authors: RP
authors: Wallin
authors: Niklas K
authors: NK
authors: Björkström
authors: Mikael
authors: M
authors: Björnstedt
authors: Anders
authors: A
authors: Hjerpe
authors: Hans-Gustaf
authors: HG
authors: Ljunggren
authors: Katalin
authors: K
authors: Dobra
authors: Karl-Johan
authors: KJ
authors: Malmberg
authors: Mattias
authors: M
authors: Carlsten
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology / Q000378:metabolism; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000276:immunology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018038:Sodium Selenite / Q000494:pharmacology*; D000097625:HLA-E Antigens
chemical_list: D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D018038:Sodium Selenite; D000097625:HLA-E Antigens; C497869:KLRD1 protein, human