DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells

Mol Cell. 2021 Apr 1;81(7):1469-1483.e8. doi: 10.1016/j.molcel.2021.01.038. Epub 2021 Feb 19.


We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8+ T cells. In vivo HMA treatment promotes CD8+ T cell tumor infiltration and suppresses tumor growth via CD8+ T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8+ T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8+ T cell subpopulations, increasing both the number and abundance of a granzyme Bhigh, perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response.

Keywords: CD8+ T cells; DNA methylation; NFATc1; cytolytic activity; decitabine; epigenetic therapy; granzyme B; killing potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • CpG Islands / immunology*
  • DNA Methylation / drug effects*
  • DNA Methylation / immunology
  • Decitabine / pharmacology*
  • Granzymes / immunology*
  • Humans
  • Lymphocyte Activation / drug effects*
  • NFATC Transcription Factors / immunology
  • Perforin / immunology


  • NFATC Transcription Factors
  • NFATC1 protein, human
  • Perforin
  • Decitabine
  • GZMB protein, human
  • Granzymes