Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity

Oncogene. 2015 Dec 3;34(49):5960-70. doi: 10.1038/onc.2015.46. Epub 2015 Mar 9.

Abstract

The poor efficacy of the in vivo anti-tumor immune response has been partially attributed to ineffective T-cell responses mounted against the tumor. Fas-FasL-dependent activation-induced cell death (AICD) of T cells is believed to be a major contributor to compromised anti-tumor immunity. The molecular mechanisms of AICD are well-investigated, yet the possibility of regulating AICD for cancer therapy remains to be explored. In this study, we show that histone deacetylase inhibitors (HDACIs) can inhibit apoptosis of CD4(+) T cells within the tumor, thereby enhancing anti-tumor immune responses and suppressing melanoma growth. This inhibitory effect is specific for AICD through suppressing NFAT1-regulated FasL expression on activated CD4(+) T cells. In gld/gld mice with mutation in FasL, the beneficial effect of HDACIs on AICD of infiltrating CD4(+) T cells is not seen, confirming the critical role of FasL regulation in the anti-tumor effect of HDACIs. Importantly, we found that the co-administration of HDACIs and anti-CTLA4 could further enhance the infiltration of CD4(+) T cells and achieve a synergistic therapeutic effect on tumor. Therefore, our study demonstrates that the modulation of AICD of tumor-infiltrating CD4(+) T cells using HDACIs can enhance anti-tumor immune responses, uncovering a novel mechanism underlying the anti-tumor effect of HDACIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / administration & dosage*
  • Antibodies / therapeutic use
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects*
  • CTLA-4 Antigen / antagonists & inhibitors*
  • Cell Death
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase Inhibitors / administration & dosage*
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / pharmacology
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / immunology
  • Mice
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism

Substances

  • Antibodies
  • Antineoplastic Agents
  • CTLA-4 Antigen
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • NFATC Transcription Factors
  • Nfatc2 protein, mouse
  • trichostatin A