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Defective Interferon Gamma Production by Tumor-Specific CD8+ T Cells Is Associated With 5'Methylcytosine-Guanine Hypermethylation of Interferon Gamma Promoter.


ABSTRACT: Interferon gamma (IFN?) 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 IFN? expression and production upon activation. Assessment of the relationship between IFN? production and the 5'methylcytosine-guanine (CpG) dinucleotide methylation of the IFN? promoter using bisulfite treatment has shown that IFN?- 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 IFN? methylation inversely correlates with transcription, protein level, and cytotoxicity. Altogether, we propose that a sizeable portion of human tumor-specific CTLs are deficient in IFN? response, contributed by CpG hypermethylation of the IFN? promoter. Our findings have important implications for immunotherapy strategies and for methods to detect human antigen-specific T cells.

SUBMITTER: Abd Hamid M 

PROVIDER: S-EPMC7066077 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Defective Interferon Gamma Production by Tumor-Specific CD8<sup>+</sup> T Cells Is Associated With 5'Methylcytosine-Guanine Hypermethylation of Interferon Gamma Promoter.

Abd Hamid Megat M   Yao Xuan X   Waugh Craig C   Rosendo-Machado Samara S   Li Chris C   Rostron Timothy T   Frankland John J   Peng Yanchun Y   Dong Tao T  

Frontiers in immunology 20200305


Interferon gamma (IFNγ) supports effector responses of CD8<sup>+</sup> 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<sup>-</sup> CTL clones accumulates C  ...[more]

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