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

Genome Biol. 2019 Dec 31;21(1):2. doi: 10.1186/s13059-019-1921-y.


Background: Tumor-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.

Results: In 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.

Conclusion: Our 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.

Keywords: Bystanders; Colorectal cancer; Methylome; T cell exhaustion; Transcription factor; Transcriptome; Tumor-reactive T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / metabolism*
  • Colorectal Neoplasms / immunology*
  • DNA Methylation*
  • Epigenesis, Genetic
  • Humans
  • Transcription Factors / metabolism
  • Transcriptome*


  • Transcription Factors