Epigenetic regulations in the IFNγ signalling pathway: IFNγ-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes

Abstract

Downregulation of MHC class I expression on tumour cells, a common mechanism by which tumour cells can escape from specific immune responses, can be associated with coordinated silencing of antigen-presenting machinery genes. The expression of these genes can be restored by IFNγ. In this study we documented association of DNA demethylation of selected antigen-presenting machinery genes located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells in several MHC class I-deficient murine tumour cell lines (TC-1/A9, TRAMP-C2, MK16 and MC15). Our data also documented higher methylation levels in these genes in TC-1/A9 cells, as compared to their parental MHC class I-positive TC-1 cells. IFNγ-mediated DNA demethylation was relatively fast in comparison with demethylation induced by DNA methyltransferase inhibitor 5-azacytidine, and associated with increased histone H3 acetylation in the promoter regions of APM genes. Comparative transcriptome analysis in distinct MHC class I-deficient cell lines upon their treatment with either IFNγ or epigenetic agents revealed that a set of genes, significantly enriched for the antigen presentation pathway, was regulated in the same manner. Our data demonstrate that IFNγ acts as an epigenetic modifier when upregulating the expression of antigen-presenting machinery genes.

Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

“…Treatment of mesenchymal cell lines with IFNγ led to up-regulation of the immunoproteasome and induces pSTAT1. IFNγ plays key roles in tumor immune surveillance, can act as an epigenetic modifier to up-regulate gene expression, and has been investigated as a treatment for various cancers (37,38). As we have shown that immunoproteasome downregulation may occur through an epigenetic or a STAT1/STAT3 dependent mechanism, IFNγ treatment may act at multiple points to overcome this inhibition.…”

The urgent need to recover MHC class I in cancers for effective immunotherapy

“…In several recent papers, such regulation at the epigenetic level was shown to be able to synergize with immunotherapy for the eradication of mouse tumor models [48, 49, 50•]. Interestingly, IFN-γ-induced restoration of ‘soft’ lesions of MHC-I, one of the most powerful inducers of this gene, was shown to partly mediate its effect by inducing demethylation of antigen-processing machinery related genes, including the TAP genes and LMP-2 [51]. …”

Antigen processing and immune regulation in the response to tumours

“…These encompass almost all the components of the APP and while inducing down‐regulation of MHC I they also alter the repertoire of antigenic peptides presented to CTL. Interestingly, IFN‐ γ stimulation is able to restore expression of antigen‐processing machinery (APM) in cancer cell lines, suggesting that targeting these components and modulating their expression may provide immunotherapeutic strategies to increase the visibility of cancerous cells and allow recruitment of specialized immune cells to target and eliminate cancer …”