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Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma

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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.

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Abbreviations

ACTB:

Beta-actin

ChIP:

Chromatin immunoprecipitation

GM:

Geometric mean

HDAC:

Histone deacetylase

HDACi:

Histone deacetylase inhibitor(s)

IRF1:

Interferon response factor 1

MCL:

Mantle cell lymphoma

NKT:

Natural killer T

P/I:

Phorbol 12-myristate 13-acetate and ionomycin

TSA:

Trichostatin-A

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Acknowledgments

This work was supported by NIH/National Cancer Institute (NCI) 1R21CA162277, R21CA184469, and R21CA199544 grants to Tonya Webb and the American Association of Immunologists (AAI) Careers in Immunology Fellowship to Irina Tiper.

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  1. Department 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

    Irina V. Tiper & Tonya J. Webb

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  1. Irina V. Tiper
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  2. Tonya J. Webb
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Correspondence to Tonya J. Webb.

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Tiper, I.V., Webb, T.J. Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma. Cancer Immunol Immunother 65, 1411–1421 (2016). https://doi.org/10.1007/s00262-016-1900-z

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