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

Li Shen, Michael Ciesielski, Swathi Ramakrishnan, Kiersten M. Miles, Leigh Ellis, Paula Sotomayor, Protul Shrikant, Robert Fenstermaker, Roberto Pili

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere30815
JournalPLoS One
Volume7
Issue number1
DOIs
StatePublished - Jan 27 2012
Externally publishedYes

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kidney neoplasms
histone deacetylase
Histone Deacetylase Inhibitors
T-cells
Kidney Neoplasms
immunotherapy
prostatic neoplasms
Regulatory T-Lymphocytes
Immunotherapy
Prostatic Neoplasms
T-lymphocytes
kidney cells
vaccines
interleukin-2
neoplasms
carcinoma
immunosuppressive agents
mice
acetylation
castration

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Class I Histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. / Shen, Li; Ciesielski, Michael; Ramakrishnan, Swathi; Miles, Kiersten M.; Ellis, Leigh; Sotomayor, Paula; Shrikant, Protul; Fenstermaker, Robert; Pili, Roberto.

In: PLoS One, Vol. 7, No. 1, e30815, 27.01.2012.

Research output: Contribution to journalArticle

Shen, L, Ciesielski, M, Ramakrishnan, S, Miles, KM, Ellis, L, Sotomayor, P, Shrikant, P, Fenstermaker, R & Pili, R 2012, 'Class I Histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models', PLoS One, vol. 7, no. 1, e30815. https://doi.org/10.1371/journal.pone.0030815
Shen, Li ; Ciesielski, Michael ; Ramakrishnan, Swathi ; Miles, Kiersten M. ; Ellis, Leigh ; Sotomayor, Paula ; Shrikant, Protul ; Fenstermaker, Robert ; Pili, Roberto. / Class I Histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. In: PLoS One. 2012 ; Vol. 7, No. 1.
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AU - Ellis, Leigh

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