Selenite induces posttranscriptional blockade of HLA-E expression and sensitizes tumor cells to CD94/NKG2A-positive NK cells

J Immunol. 2011 Oct 1;187(7):3546-54. doi: 10.4049/jimmunol.1100610. Epub 2011 Sep 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Separation
  • Cytotoxicity, Immunologic / immunology
  • Flow Cytometry
  • Histocompatibility Antigens Class I / biosynthesis*
  • Humans
  • Killer Cells, Natural / immunology*
  • NK Cell Lectin-Like Receptor Subfamily C / immunology
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism
  • NK Cell Lectin-Like Receptor Subfamily D / immunology
  • NK Cell Lectin-Like Receptor Subfamily D / metabolism
  • Oxidative Stress / immunology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium Selenite / pharmacology*

Substances

  • Antineoplastic Agents
  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • KLRD1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily D
  • Sodium Selenite