Comparison of the immune effects of different HDAC inhibitors

Authors

• C Celades
• J Schlom
• RN Donahue

Abstract

Epigenetic silencing of tumor and immune genes via histone deacetylation (HDAC), is implicated in cancer. Five HDAC inhibitors (HDACi) are FDA approved for hematologic malignancies but have limited activity in solid tumors. Preclinical studies, however, show enhanced therapeutic potential of HDACi combined with immune mediating agents; the HDACi Entinostat synergizes with a tumor targeting immunocytokine (NHS-IL12), generating potent anti-tumor activity, including in anti-PD-1/PD-L1 resistant tumors with MHC-1 and APM deficiencies. We compared the immune effects of two experimental class I HDACi’s, Entinostat and Zabadinostat, and two FDA approved pan-HDACi’s, Vorinostat and Panobinostat, to elucidate their potential for combination with immunocytokines. Peripheral blood mononuclear cells from 7 healthy donors were treated with clinically relevant exposures of HDACi and examined by flow cytometry for 158 immune cell subsets and expression of epigenetic marks. While total CD4+T, CD8+T and NK cells were unchanged by Entinostat, Zabadinostat, and Vorinostat, these HDACi increased frequencies of multiple activated CD4+ and CD8+T and NK cell subsets; however, only Entinostat and Zabadinostat increased NK cells expressing NKG2D (activating receptor). All HDACi tested reduced total Tregs, including those with a more suppressive phenotype. Many more immune changes were seen only with Panobinostat, including reductions in NK subsets. Expression of epigenetic acetylation marks associated with transcriptional activation (H3K27ac, H3K9ac) were increased in most PBMC subsets with all HDACi tested except for Vorinostat. Overall, similar immune potentiating effects were noted with Entinostat, Zabadinostat and Vorinostat, and support the rationale to evaluate these HDACi with immunocytokines in both preclinical and clinical studies.

Scientific Focus Area: Clinical Research

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