Novel Role for STAT3 in Transcriptional Regulation of NK Immune Cell Targeting Receptor MICA on Cancer Cells

Abstract

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-g production in a TGF-b1-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. Cancer Res; 71(5); 1615-26. Ó2011 AACR.

Inhibition of Glycogen Synthase Kinase-3 Increases NKG2D Ligand MICA Expression and Sensitivity to NK Cell–Mediated Cytotoxicity in Multiple Myeloma Cells: Role of STAT3

“…7). Interestingly, STAT3 constitutive activation was shown to prevent the induction of MICA following genotoxic stress (24). These observations suggest that constitutive activation of this transcription factor in MM cells may interfere with pathways triggered by DDR; thus, GSK3 inhibition may favor MICA upregulation after melphalan treatment by reducing the repressive activity of STAT3.…”

“…Moreover, we found that MICA upregulation correlates with an increased gene promoter activity and a reduction of the Tyr 705 phosphorylation and MICA promoter binding of the transcription factor STAT3, a negative regulator of MICA transcription (24).…”

“…Interestingly, a pivotal role in this regulatory mechanism is mediated by the effect of GSK3 on STAT3 activation, a transcription factor recently described to specifically inhibit MICA gene expression in different cancer cell lines, via direct repression of its promoter activity (24). Moreover, STAT3 can be persistently activated in different types of human cancers, including MM, where it plays critical roles in the process of carcinogenesis and tumor survival (36,49,50), also sustaining local tumor-promoting stromal inflammation (51).…”

“…To determine whether one of the mechanisms involved in the upregulation of MICA gene expression could be a direct regulatory action mediated by STAT3 on its promoter activity, quantitative ChIP assays were done on the promoter region encompassing the repressor element MICA/STAT3-RE (24). As shown in Fig.…”

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

“…20,29,32,37,[41][42][43] NKG2D ligands are often upregulated on a wide range of tumor cells in response to cellular stress during malignant transformation. However, as tumors progress, soluble MICA/B or ULBPs are often shed from the membranes of tumor cells.…”