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Updated: Mar 15, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma
1Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, HSF I-Rm 380, 685 W Baltimore St, Baltimore, MD, 21201, USA.
Abstract:
Histone deacetylases (HDACs) are a family of enzymes that influence expression of genes implicated in tumor initiation, progression, and anti-tumor responses. In addition to their canonical role in deacetylation of histones, HDACs regulate many non-canonical targets, such as Signal Transducer and Activator of Transcription 3 (STAT3). We hypothesize that tumors use epigenetic mechanisms to dysregulate CD1d-mediated antigen presentation, thereby impairing the ability of natural killer T (NKT) cells to recognize and destroy malignant cells. In this study, we pre-treated CD1d-expressing tumor cells with HDAC inhibitors (HDACi) and assessed CD1d-dependent NKT cell responses to mantle cell lymphoma (MCL). Pre-treatment with Trichostatin-A, a pan-HDACi, rapidly enhanced both CD1d- and MHC class II-mediated antigen presentation. Similarly, treatment of MCL cells with other HDACi resulted in enhanced CD1d-dependent NKT cell responses. The observed changes are due, at least in part, to an increase in both CD1D mRNA and CD1d cell surface expression. Mechanistically, we found that HDAC2 binds to the CD1D promoter. Knockdown of HDAC2 in tumor cells resulted in a significant increase in CD1d-mediated antigen presentation. In addition, treatment with HDACi inhibited STAT3 and STAT3-regulated inflammatory cytokine secretion by MCL cells. We demonstrated that MCL-secreted IL-10 inhibits CD1d-mediated antigen presentation and pre-treatment with TSA abrogates secretion of IL-10 by MCL. Taken together, our studies demonstrate the efficacy of HDACi in restoring anti-tumor responses to MCL through both cell-intrinsic and cell-extrinsic mechanisms and strongly implicate a role for HDACi in enhancing immune responses to cancer.
Insights
Histone deacetylase inhibitors (HDACi) enhance anti-tumor immunity by boosting CD1d-mediated antigen presentation in mantle cell lymphoma. These epigenetic drugs restore natural killer T (NKT) cell recognition and anti-cancer responses.
Area of Science:
- Immunology
- Epigenetics
- Oncology
Background:
- Histone deacetylases (HDACs) regulate gene expression, impacting cancer development and immune responses.
- Tumors can evade immune detection by disrupting antigen presentation pathways, such as CD1d-mediated presentation to natural killer T (NKT) cells.
- Signal Transducer and Activator of Transcription 3 (STAT3) is a target of HDACs and plays a role in inflammatory cytokine secretion.
Purpose of the Study:
- To investigate if HDAC inhibitors (HDACi) can restore CD1d-mediated antigen presentation and enhance NKT cell anti-tumor responses in mantle cell lymphoma (MCL).
- To elucidate the molecular mechanisms by which HDACi affect CD1d expression and NKT cell activation in MCL.
- To assess the impact of HDACi on STAT3 signaling and related cytokine secretion in MCL.
Main Methods:
- Mantle cell lymphoma (MCL) cells were pre-treated with HDAC inhibitors (e.g., Trichostatin-A).
- CD1d- and MHC class II-mediated antigen presentation to NKT cells was assessed.
- CD1D mRNA and cell surface expression levels were quantified.
- HDAC2 binding to the CD1D promoter was analyzed, and HDAC2 was knocked down.
- STAT3 signaling and inflammatory cytokine secretion (e.g., IL-10) were measured.
Main Results:
- Trichostatin-A and other HDAC inhibitors rapidly enhanced CD1d- and MHC class II-mediated antigen presentation in MCL cells.
- HDAC inhibition increased CD1D mRNA and cell surface CD1d expression.
- HDAC2 was found to bind the CD1D promoter, and its knockdown significantly increased CD1d-mediated antigen presentation.
- HDACi treatment inhibited STAT3 signaling and reduced secretion of inflammatory cytokines like IL-10.
- HDACi treatment abrogated IL-10 secretion, which was shown to inhibit CD1d-mediated antigen presentation.
Conclusions:
- HDAC inhibitors are effective in restoring anti-tumor responses against mantle cell lymphoma (MCL) through both cell-intrinsic and cell-extrinsic mechanisms.
- HDACi enhance anti-cancer immunity by upregulating CD1d-mediated antigen presentation and NKT cell activity.
- These findings strongly support the potential of HDAC inhibitors as a therapeutic strategy to augment anti-tumor immune responses in cancer.
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