RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma

Cancer Res. 2014 Apr 15;74(8):2193-2203. doi: 10.1158/0008-5472.CAN-13-1703. Epub 2014 Mar 3.

Abstract

The immunoreceptor NKG2D originally identified in natural killer (NK) cells recognizes ligands that are upregulated on tumor cells. Expression of NKG2D ligands (NKG2DL) is induced by the DNA damage response (DDR), which is often activated constitutively in cancer cells, revealing them to NK cells as a mechanism of immunosurveillance. Here, we report that the induction of retinoic acid early transcript 1 (RAE1) ligands for NKG2D by the DDR relies on a STING-dependent DNA sensor pathway involving the effector molecules TBK1 and IRF3. Cytosolic DNA was detected in lymphoma cell lines that express RAE1 and its occurrence required activation of the DDR. Transfection of DNA into ligand-negative cells was sufficient to induce RAE1 expression. Irf3(+/-);Eμ-Myc mice expressed lower levels of RAE1 on tumor cells and showed a reduced survival rate compared with Irf3(+/+);Eμ-Myc mice. Taken together, our results suggest that genomic damage in tumor cells leads to activation of STING-dependent DNA sensor pathways, thereby activating RAE1 and enabling tumor immunosurveillance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA Damage / genetics*
  • DNA Damage / physiology*
  • DNA Damage / radiation effects
  • DNA, Neoplasm / metabolism*
  • Immunologic Surveillance
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Regulatory Factor-3 / metabolism
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Ligands
  • Lymphoma / genetics
  • Lymphoma / immunology
  • Lymphoma / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily K / genetics
  • NK Cell Lectin-Like Receptor Subfamily K / immunology
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Nuclear Matrix-Associated Proteins / biosynthesis
  • Nuclear Matrix-Associated Proteins / genetics
  • Nuclear Matrix-Associated Proteins / immunology
  • Nuclear Matrix-Associated Proteins / metabolism*
  • Nucleocytoplasmic Transport Proteins / biosynthesis
  • Nucleocytoplasmic Transport Proteins / genetics
  • Nucleocytoplasmic Transport Proteins / immunology
  • Nucleocytoplasmic Transport Proteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism
  • Transfection
  • Up-Regulation

Substances

  • DNA, Neoplasm
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Klrk1 protein, mouse
  • Ligands
  • MPYS protein, mouse
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Nuclear Matrix-Associated Proteins
  • Nucleocytoplasmic Transport Proteins
  • Rae1 protein, mouse
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases