Distinct epigenetic features of tumor-reactive CD8+ T cells in colorectal cancer patients revealed by genome-wide DNA methylation analysis

Abstract

BackgroundTumor-reactive CD8+ tumor-infiltrating lymphocytes (TILs) represent a subtype of T cells that can recognize and destroy tumor specifically. Understanding the regulatory mechanism of tumor-reactive CD8+ T cells has important therapeutic implications. Yet the DNA methylation status of this T cell subtype has not been elucidated.ResultsIn this study, we segregate tumor-reactive and bystander CD8+ TILs, as well as naïve and effector memory CD8+ T cell subtypes as controls from colorectal cancer patients, to compare their transcriptome and methylome characteristics. Transcriptome profiling confirms previous conclusions that tumor-reactive TILs have an exhausted tissue-resident memory signature. Whole-genome methylation profiling identifies a distinct methylome pattern of tumor-reactive CD8+ T cells, with tumor-reactive markers CD39 and CD103 being specifically demethylated. In addition, dynamic changes are observed during the transition of naïve T cells into tumor-reactive CD8+ T cells. Transcription factor binding motif enrichment analysis identifies several immune-related transcription factors, including three exhaustion-related genes (NR4A1, BATF, and EGR2) and VDR, which potentially play an important regulatory role in tumor-reactive CD8+ T cells.ConclusionOur study supports the involvement of DNA methylation in shaping tumor-reactive and bystander CD8+ TILs, and provides a valuable resource for the development of novel DNA methylation markers and future therapeutics.

Differential gene expression of tumor-infiltrating CD4 + T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis

“…44 Moreover, changes in global DNA methylation patterns of TILs influence CRC progression from onset to metastasis. 45 Herein, we found that T cell proliferation and differentiation-and cell cycle-related genes were significantly downregulated and chromatin-mediated epigenetic silencing pathways were upregulated in advanced stages of CRC, compared with early stages. These data suggest that chromatin-silencing plays an indispensable role in the progression of CRC.…”

Role of Methylation in Pro- and Anti-Cancer Immunity

“…CD8 + TILs become exhausted and lose their effector functions in the TME due to numerous factors, such as immunosuppressive mechanisms by tumor cells. Analyzing the transcriptome and methylome of CD8 + TILs in the TME of colorectal cancer simultaneously, Yang et al confirmed tumor-reactive TILs have an exhausted tissue-resident memory signature [ 117 ]. They showed tumor-reactive markers CD39 and CD103 of CD8 + TILs were demethylated and CD8 + TILs had an exhausted phenotype, including high expression of CTLA4, HAVCR2, LAYN, and TOX [ 117 , 118 ].…”

High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39+CD8+ T cells

“…CD8 + T cells plays an important role of specifically recognising and killing tumour cells via releasing cytotoxic molecules in antitumour immune response, whereas only part of CD8 + tumour infiltrating lymphocytes (TILs) can recognise tumour-specific neoantigen and achieve targeted killing. Recently, increasing evidence has shown that CD39 is a marker of tumour-specific T cells, [13][14][15] though it was considered to be a biomarker of exhausted T cells in some studies. They found that CD39 + CD8 + T cells had stronger antitumour ability than CD39 − CD8 + T cells in six different malignant tumour types.…”