AUTHOR=Abd Hamid Megat , Yao Xuan , Waugh Craig , Rosendo-Machado Samara , Li Chris , Rostron Timothy , Frankland John , Peng Yanchun , Dong Tao 

TITLE=Defective Interferon Gamma Production by Tumor-Specific CD8+ T Cells Is Associated With 5′Methylcytosine-Guanine Hypermethylation of Interferon Gamma Promoter

JOURNAL=Frontiers in Immunology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00310

DOI=10.3389/fimmu.2020.00310

ISSN=1664-3224

ABSTRACT=Interferon gamma (IFNγ) supports effector responses of CD8+ cytotoxic T lymphocytes (CTL), and a surrogate marker for detection of antigen-specific T cells. Here, we show that tumor-specific CTL clones have impaired IFNγ expression and production upon activation. Assessing the relationship between IFNγ production and the 5’methylcytosine-guanine (CpG) dinucleotide methylation of the IFNγ promoter using bisulphite treatment shown that IFNγ- CTL clones accumulates CpG hypermethylation within the promoter at key transcription factor binding sites (-186 and -54), known to be vital for transcription. We confirmed these findings using ex-vivo isolated and short-term expanded bulk tumor-specific CTL lines from four cancer patients and demonstrated that IFNγ methylation inversely correlates with transcription, protein level and cytotoxicity. Altogether, we propose that human tumor-specific CTLs are deficient in IFNγ response due to hypermethylation of the IFNγ promoter. Our findings have important implications for immunotherapy strategies and for methods to detect antigen-specific T cells.