Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma.
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.
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
IV
Tiper
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. twebb@som.umaryland.edu.
Tonya J
TJ
Webb
D017951:Antigen Presentation; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D016233:Immunotherapy, Active / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D020522:Lymphoma, Mantle-Cell / Q000276:immunology / Q000628:therapy*; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D055610:Antigens, CD1d; D000970:Antineoplastic Agents; C526877:CD1D protein, human; D000949:Histocompatibility Antigens Class II; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C508609:IL10 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; C012589:trichostatin A; D007371:Interferon-gamma
CD1d; Cancer; Epigenetics; HDAC inhibitors; Immunotherapy; NKT cells