Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells.
The role of natural killer group 2, member D receptor (NKG2D)-expressing natural killer (NK) cells in tumor immunosurveillance is now well established. Nevertheless, tumor progression occurs despite tumor immunosurveillance, leading to cancer persistence in immunocompetent hosts. STAT3 plays a pivotal role both in oncogenic functions and in immunosuppression. In this study, we investigated the role of STAT3 in suppressing NK cell-mediated immunosurveillance. Using a colorectal cancer cell line (HT29) that can poorly activate NK, we neutralized STAT3 with pharmacologic inhibitors or siRNA and found that this led to an increase in NK degranulation and IFN-γ production in a TGF-β1-independent manner. Exposure to NKG2D-neutralizing antibodies partially restored STAT3 activity, suggesting that it prevented NKG2D-mediated NK cell activation. On this basis, we investigated the expression of NKG2D ligands after STAT3 activation in HT29, mesenchymal stem cells, and activated lymphocytes. The NK cell recognition receptor MHC class I chain-related protein A (MICA) was upregulated following STAT3 neutralization, and a direct interaction between STAT3 and the MICA promoter was identified. Because cross-talk between DNA damage repair and NKG2D ligand expression has been shown, we assessed the influence of STAT3 on MICA expression under conditions of genotoxic stress. We found that STAT3 negatively regulated MICA expression after irradiation or heat shock, including in lymphocytes activated by CD3/CD28 ligation. Together, our findings reveal a novel role for STAT3 in NK cell immunosurveillance by modulating the MICA expression in cancer cells.
INSERM (Institut National de la Santé et de la Recherche Médicale) UMR 645, Besançon, France.
Romain
R
Bedel
Antoine
A
Thiery-Vuillemin
Camille
C
Grandclement
Jeremy
J
Balland
Jean-Paul
JP
Remy-Martin
Bernadette
B
Kantelip
Jean-René
JR
Pallandre
Xavier
X
Pivot
Christophe
C
Ferrand
Pierre
P
Tiberghien
Christophe
C
Borg
D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D019073:HT29 Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007157:Immunologic Surveillance / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016297:Mutagenesis, Site-Directed; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology* / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human