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

• Published in: Frontiers in immunology 2020-03, Vol.11
• Main Authors: Abd Hamid, Megat, Yao, Xuan, Waugh, Craig, Rosendo-Machado, Samara, Li, Chris, Rostron, Timothy, Frankland, John, Peng, Yanchun, Dong, Tao
• Format: Article
• Language: English
• Subjects: CD8+ T cells; Immunology; interferon gamma; methylation; mRNA; promoter; response
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.00310

Interferon gamma (IFNγ) supports effector responses of CD8 + cytotoxic T lymphocytes (CTLs) and is 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. Assessment of the relationship between IFNγ production and the 5′methylcytosine-guanine (CpG) dinucleotide methylation of the IFNγ promoter using bisulfite treatment has 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 a sizeable portion of human tumor-specific CTLs are deficient in IFNγ response, contributed by CpG hypermethylation of the IFNγ promoter. Our findings have important implications for immunotherapy strategies and for methods to detect human antigen-specific T cells.