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

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.

• Authors: K Cao, G Wang, W Li, L Zhang, R Wang, Y Huang, L Du, J Jiang, C Wu, X He, A I Roberts, F Li, A B Rabson, Y Wang, Y Shi
• Journal: Oncogene (Oncogene) Vol. 34 Issue 49 Pg. 5960-70 (Dec 03 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 25745993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Antibodies (administration & dosage, therapeutic use)
• Antineoplastic Agents (administration & dosage, 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, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
• Humans
• Hydroxamic Acids (administration & dosage, pharmacology)
• Melanoma, Experimental (drug therapy, immunology)
• Mice
• NFATC Transcription Factors (genetics, metabolism)