Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models.

Abstract

BACKGROUND:

Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been reported to have antitumor activity in different malignancies and immunomodulatory effects. Herein, we report the Tregs-targeting and immune-promoting effect of a class I specific HDAC inhibitor, entinostat, in combination with either IL-2 in a murine renal cell carcinoma (RENCA) model or a survivin-based vaccine therapy (SurVaxM) in a castration resistant prostate cancer (CR Myc-CaP) model.

METHODS AND RESULTS:

RENCA or CR Myc-CaP tumors were implanted orthotopically or subcutaneously, respectively. Inoculated mice were randomized into four treatment groups: vehicle, entinostat, cytokine or vaccine, and combination. Tregs in the blood were assessed by FACS analysis. Real time quantitative PCR and Western blot analysis of isolated T cell subpopulations from spleen were performed to determine Foxp3 gene and protein expression. The suppressive function of Tregs was tested by T cell proliferation assay. Low dose (5 mg/kg) entinostat reduced Foxp3 levels in Tregs and this was associated with enhanced tumor growth inhibition in combination with either IL-2 or a SurVaxM vaccine. Entinostat down-regulated Foxp3 expression transcriptionally and blocked Tregs suppressive function without affecting T effector cells (Teffs). In vitro low dose entinostat (0.5 µM) induced STAT3 acetylation and a specific inhibitor of STAT3 partially rescued entinostat-induced down-regulation of Foxp3, suggesting that STAT3 signaling is involved in Foxp3 down-regulation by entinostat.

CONCLUSIONS:

These results demonstrate a novel immunomodulatory effect of class I HDAC inhibition and provide a rationale for the clinical testing of entinostat to enhance cancer immunotherapy.

• Authors: Li Shen, Michael Ciesielski, Swathi Ramakrishnan, Kiersten M Miles, Leigh Ellis, Paula Sotomayor, Protul Shrikant, Robert Fenstermaker, Roberto Pili
• Journal: PloS one (PLoS One) Vol. 7 Issue 1 Pg. e30815 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22303460 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzamides
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Histone Deacetylase Inhibitors
• Interleukin-2
• Pyridines
• STAT3 Transcription Factor
• Vaccines, Subunit
• entinostat
• Interferon-gamma
• Histone Deacetylases

Topics

• Acetylation (drug effects)
• Animals
• Benzamides (pharmacology, therapeutic use)
• CD8-Positive T-Lymphocytes (immunology)
• Carcinoma, Renal Cell (drug therapy, genetics, immunology, pathology)
• Castration
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Histone Deacetylases (metabolism)
• Humans
• Immunity (drug effects)
• Immunotherapy
• Interferon-gamma (immunology)
• Interleukin-2 (therapeutic use)
• Kidney Neoplasms (drug therapy, genetics, immunology, pathology)
• Lymphocyte Depletion
• Male
• Mice
• Prostatic Neoplasms (drug therapy, genetics, immunology, pathology)
• Pyridines (pharmacology, therapeutic use)
• STAT3 Transcription Factor (metabolism)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Vaccines, Subunit (immunology, therapeutic use)