Abstract
Expression of MHC class II pathway proteins in ovarian cancer correlates with prolonged survival. Murine and human ovarian cancer cells were treated with epigenetic modulators – histone deacetylase inhibitors and a DNA methyltransferase inhibitor. mRNA and protein expression of the MHC II pathway were evaluated by qPCR and flow cytometry. Treatment with entinostat and azacytidine of ID8 cells in vitro increased mRNA levels of Cd74, Ciita, and H2-Aa, H2-Eb1. MHC II and CD74 protein expression were increased after treatment with either agent. A dose dependent response in mRNA and protein expression was seen with entinostat. Combination treatment showed higher MHC II protein expression than with single agent treatment. In patient derived xenografts, CIITA, CD74, and MHC II mRNA transcripts were significantly increased after combination treatment. Expression of MHC II on ovarian tumors in MISIIR-Tag mice was increased with both agents relative to control. Combination treatment significantly reduced ID8 tumor growth in immune-competent mice. Epigenetic treatment increases expression of MHC II on ovarian cancer cells and impedes tumor growth. This approach warrants further study in ovarian cancer patients.
Highlights
Immunotherapy has transformed cancer treatment in several malignancies over the last decade
To evaluate effects of Histone deacetylase inhibitors (HDACi) and DNA methyltranferase inhibitors (DNMTi) on major histocompatibility complex 2 (MHC II) pathway upregulation and growth of ovarian cancer (OVCA) tumors, we focused our efforts on the agents panobinostat, entinostat and azacytidine to facilitate future translatability
To select appropriate doses of epigenetic modifiers for use in evaluating effects on the MHC II pathway, ATPlite assays were performed on both the ID8 murine cell line and three human OVCA cell lines: SKOV3.IP, A2780.CP20, A2780
Summary
Immunotherapy has transformed cancer treatment in several malignancies over the last decade. Augmenting preexisting immune responses or blocking immune inhibition has shown improvements in overall survival in melanoma [1], multiple myeloma [2], and renal-cell carcinoma [3]. While OVCA is not highly immunogenic, increased levels of immune effector cells within the tumor correlates with better anti-tumor responses and improved survival [6,7,8]. Epigenetic modulation, such as histone deacetylation and DNA methylation, produces non-sequence DNA changes that affect transcription and translation. Panobinostat is a non-selective HDACi that is FDA-approved for the treatment of multiple myeloma. HDACi have been shown to activate antitumor immunity, including the major histocompatibility complex 2 (MHC II) pathway [12,13,14,15,16]
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