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

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 pretreatment 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 extrinsic mechanisms and strongly implicate a role for HDACi in enhancing immune responses to cancer.

Trichostatin A Sensitizes Hepatocellular Carcinoma Cells to Enhanced NK Cell-mediated Killing by Regulating Immune-related Genes

“…Inhibition of the expression of the MHC class I-associated genes, TAP1, TAP2, LMP2, LMP7, and Tapasin, makes it difficult for CD8 + T cells to recognize tumor cells (36). Similarly, downregulation of CD1d on tumor cells makes it difficult for NKT cells to respond to tumor cells (35). This immune depression in the respective tumor cells limits recognition by CD8 + T cells and NKT cells and is thought to be a critical strategy for tumor growth and survival.…”

“…There are several recent reports that show an unexpected effect of TSA in regulating the immune system in various tumors (35,36). For example, HDACs are known to play critical roles in the immune escape mechanism of several tumor cells, such as melanoma cells and lymphoma cells (35,36). In melanoma cells (B16F10 cells), HDACs were shown to have a role in the reduction of MHC class I-associated antigen processing and presentation.…”

“…However, the effect of the immune system on tumor development is also important (31,32,33,34). There are several recent reports that show an unexpected effect of TSA in regulating the immune system in various tumors (35,36). For example, HDACs are known to play critical roles in the immune escape mechanism of several tumor cells, such as melanoma cells and lymphoma cells (35,36).…”

Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells

“…Histone deacetylase inhibitors are known to increase MHC class I and II expression on the cell surface which would facilitate antitumor responses from both the innate and the adaptive immune systems (Nakajima et al, 2017). HDAC inhibitors have been shown to activate NK cells (Tiper & Webb, 2016). Other studies have linked HDAC inhibitors to both increased and decreased expression of PD-L1 and PD-L2 on tumor cells with the differential effects appearing to be dependent on HDAC inhibitor dose or the cell lines being tested, though all studies argue that HDAC inhibitors enhance the antitumor responses of the immune system using checkpoint inhibitory antibodies (Beg & Gray, 2016; Shen, Orillion, & Pili, 2016; Terranova-Barberio, Thomas, & Munster, 2016; Yang et al, 2015; Zheng etal.,2016).…”

The renaissance of anti‐neoplastic immunity from tumor cell demise

“…Targeted therapies can also stimulate anti‐tumor immune responses alongside their principal mechanisms of action. HDAC inhibitors enhance CD1d gene expression on tumor cells through epigenetic mechanisms, resulting in CD1d‐mediated antigen presentation and NKT cell‐based tumor clearance . HDAC inhibitors can also promote T cell‐mediated tumor destruction by inducing T‐cell chemokine transcription, which synergizes effectively with PD‐1‐based immunotherapy .…”