Targeting the T-Cell Lymphoma Epigenome Induces Cell Death, Cancer Testes Antigens, Immune-Modulatory Signaling Pathways

Abstract

The peripheral T-cell lymphomas (PTCL) could be considered the prototypical epigenetic disease. As a disease, they are uniquely sensitive to histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors, both alone and in combination, are characterized by a host of mutations in epigenetic genes, and can develop spontaneously in genetically engineered murine models predicated on established recurring mutations in (RHOAG17V) and TET2, an epigenetic gene governing DNA methylation. Given the clinical benefit of HDAC inhibitors (HDACi) and hypomethlyation agents (HMA) alone and in combination in PTCL, we sought to explore a mechanistic basis for these agents in PTCL. Herein, we reveal profound class synergy between HDAC and DNMT inhibitors in PTCL, and that the combination induces degrees of gene expression that are substantially different and more extensive than that observed for the single agents. A prominent signature of the combination relates to the transcriptional induction of cancer testis antigens (CTA) and genes involved in the immune response. Interestingly, TBX21 and STAT4, master regulators of TH1 differentiation, were among the genes upregulated by the combination, suggesting the induction of a TH1-like phenotype. Moreover, suppression of genes involved in cholesterol metabolism and the matrisome were also identified. We believe these data provide a strong rationale for clinical studies, and future combinations leveraging an immunoepigenetic platform.

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

“…HDACs, including Trichostatin A and VPA, have been reported to induce increased expression of TAP, LMP, tapasin genes and MHC class I antigens on melanoma cells and other carcinomas [ 248 , 249 ]. Both DNMTi and HDACi induce ICD, thus releasing tumor antigens and other danger signals that activate DC and lead to the crosspriming of anti-tumor T cells and may promote Th1-like phenotype [ 228 , 250 , 251 ]. Inhibition of a G9a/DNMT network triggers ICD with a conversion of a cold tumor into a hot tumor, and antitumor immunity [ 115 ].…”

Epigenetic Priming by Hypomethylation Enhances the Immunogenic Potential of Tolinapant in T-cell Lymphoma

“…We investigated the effects of decitabine treatment on the expression of additional genes by qPCR in two human cell lines, Karpas-299 and H9. HMA treatment has been reported to re-express certain genes that are silenced by promoter methylation, such as cancer testis antigens (CTA), in human TCL cell lines ( 26 ). We selected two CTA genes ( MAGEA1 and MAGEA3 ) along with RIPK3 and interferon signaling genes (ISG), which are known to be upregulated by HMA, including IFNγ ( IFNG ; refs.…”

Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer

“…Immunoepigenetics seeks to elucidate how these epigenetic changes affect the expression of immune-related genes, the presentation of tumor antigens, and the recruitment of immune cells to the tumor site. 231 Researchers are exploring strategies to manipulate epigenetic marks to enhance the immune system's ability to target cancer cells. 230 This field also involves investigating the potential for combining epi-drugs with immunotherapies like immune checkpoint inhibitors to achieve more robust and durable responses.…”

“…Epigenetic alterations in cancer cells can influence their ability to evade immune surveillance and response. Immunoepigenetics seeks to elucidate how these epigenetic changes affect the expression of immune-related genes, the presentation of tumor antigens, and the recruitment of immune cells to the tumor site . Researchers are exploring strategies to manipulate epigenetic marks to enhance the immune system’s ability to target cancer cells .…”