Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy

Maio, Michele; Covre, Alessia; Fratta, Elisabetta; Giacomo, Anna Maria Di; Taverna, Pietro; Natali, Pier Giorgio; Coral, Sandra; Sigalotti, Luca

doi:10.1158/1078-0432.ccr-14-2914

Cited by 95 publications

(87 citation statements)

References 47 publications

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“…This study, together with our findings, indicate that regulation of chemokine expression is subject to control by multiple and distinct epigenetic mechanisms. Modulation of tumor immunogenicity by drugs that target epigenetic mechanisms may therefore represent a promising area for translational research and clinical intervention (44). …”

Section: Discussionmentioning

confidence: 99%

HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

Zheng

Zhao

Yan

et al. 2016

Clinical Cancer Research

284

219

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Purpose A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g. ~20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies which increase T cell infiltration to tumors can be efficacious in enhancing immunotherapy response. Experimental Design We performed an unbiased screen to identify FDA-approved oncology agents with ability to enhance T cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms. Results We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T cell chemokines in cancer cells, macrophages and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T cell infiltration, and T cell-dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells. Conclusions These results provide evidence for a novel role of HDACs in modulating T cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacological induction of T cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment.

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Section: Discussionmentioning

confidence: 99%

HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

Zheng

Zhao

Yan

et al. 2016

Clinical Cancer Research

284

219

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“…This mechanism of resistance could be reversed in mice, without toxicity, by combining decitabine with an inhibitor of CDA 19 . Combination of new DNA hypomethylating agents and CDA inhibitors is a new type of strategy now employed in ongoing clinical trials for several malignancies 20 . In fact, early studies using the CDA inhibitor tetrahydrouridine (THU) have shown proof of principle for combinatorial approach together with decitabine although its instability has prevented further development as a therapeutic 40 .…”

Section: Discussionmentioning

confidence: 99%

“…High expression of CDA is a distinctive feature of poor-prognosis leukemias 18 . In the liver, high CDA expression provides a “sanctuary” for cancer cells from decitabine treatment effects; this mechanism of resistance could be reversed in murine models, without increasing toxicity, by combining decitabine with an inhibitor of CDA, 19 a strategy now employed in ongoing clinical trials for myelodisplastic syndromes 20,21 . Preliminary evidence suggests that guadecitabine synergizes with other chemotherapeutics (sorafenib, oxaliplatin) in slowing down HCC cell growth in vitro 13,14 and a phase 2 clinical study evaluated guadecitabine single agent activity in patients with HCC after progression on sorafenib 22 .…”

Section: Introductionmentioning

confidence: 99%

Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma

Jueliger¹,

Lyons²,

Cannito

et al. 2016

Epigenetics

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Hepatocellular carcinoma (HCC) is a deadly malignancy characterized at the epigenetic level by global DNA hypomethylation and focal hypermethylation on the promoter of tumor suppressor genes. In most cases it develops on a background of liver steatohepatitis, fibrosis, and cirrhosis. Guadecitabine (SGI-110) is a second-generation hypomethylating agent, which inhibits DNA methyltransferases. Guadecitabine is formulated as a dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase (CDA) degradation and results in prolonged in vivo exposure to decitabine following small volume subcutaneous administration of guadecitabine. Here we found that guadecitabine is an effective demethylating agent and is able to prevent HCC progression in pre-clinical models. In a xenograft HCC HepG2 model, guadecitabine impeded tumor growth and inhibited angiogenesis, while it could not prevent liver fibrosis and inflammation in a mouse model of steatohepatitis. Demethylating efficacy of guadecitabine on LINE-1 elements was found to be the highest 8 d post-infusion in blood samples of mice. Analysis of a panel of human HCC vs. normal tissue revealed a signature of hypermethylated tumor suppressor genes (CDKN1A, CDKN2A, DLEC1, E2F1, GSTP1, OPCML, E2F1, RASSF1, RUNX3, and SOCS1) as detected by methylation-specific PCR. A pronounced demethylating effect of guadecitabine was obtained also in the promoters of a subset of tumor suppressors genes (CDKN2A, DLEC1, and RUNX3) in HepG2 and Huh-7 HCC cells. Finally, we analyzed the role of macroH2A1, a variant of histone H2A, an oncogene upregulated in human cirrhosis/HCC that synergizes with DNA methylation in suppressing tumor suppressor genes, and it prevents the inhibition of cell growth triggered by decitabine in HCC cells. Guadecitabine, in contrast to decitabine, blocked growth in HCC cells overexpressing macroH2A1 histones and with high CDA levels, despite being unable to fully demethylate CDKN2A, RUNX3, and DLEC1 promoters altered by macroH2A1. Collectively, our findings in human and mice models reveal novel epigenetic anti-HCC effects of guadecitabine, which might be effective specifically in advanced states of the disease.

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“…The hyper-methylation of tumor-suppressive genes and the hypo-methylation of oncogenes regulate the proliferation and metastasis of bladder cancer [4-6]. Therefore, the re-activation of tumor suppressors and/or the inhibition of oncogenes by modulating DNA methylation with effective and low-toxicity reagents may be a strategy for the prevention and treatment of cancer [7, 8]. …”

Section: Introductionmentioning

confidence: 99%

Kaempferol Modulates DNA Methylation and Downregulates DNMT3B in Bladder Cancer

Qiu

Lin

Zhu

et al. 2017

Cell Physiol Biochem

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Background: Genomic DNA methylation plays an important role in both the occurrence and development of bladder cancer. Kaempferol (Kae), a natural flavonoid that is present in many fruits and vegetables, exhibits potent anti-cancer effects in bladder cancer. Similar to other flavonoids, Kae possesses a flavan nucleus in its structure. This structure was reported to inhibit DNA methylation by suppressing DNA methyltransferases (DNMTs). However, whether Kae can inhibit DNA methylation remains unclear. Methods: Nude mice bearing bladder cancer were treated with Kae for 31 days. The genomic DNA was extracted from xenografts and the methylation changes was determined using an Illumina Infinium HumanMethylation 450 BeadChip Array. The ubiquitination was detected using immuno-precipitation assay. Results: Our data indicated that Kae modulated DNA methylation in bladder cancer, inducing 103 differential DNA methylation positions (dDMPs) associated with genes (50 hyper-methylated and 53 hypo-methylated). DNA methylation is mostly relied on the levels of DNMTs. We observed that Kae specifically inhibited the protein levels of DNMT3B without altering the expression of DNMT1 or DNMT3A. However, Kae did not downregulate the transcription of DNMT3B. Interestingly, we observed that Kae induced a premature degradation of DNMT3B by inhibiting protein synthesis with cycloheximide (CHX). By blocking proteasome with MG132, we observed that Kae induced an increased ubiquitination of DNMT3B. These results suggested that Kae could induce the degradation of DNMT3B through ubiquitin-proteasome pathway. Conclusion: Our data indicated that Kae is a novel DNMT3B inhibitor, which may promote the degradation of DNMT3B in bladder cancer.

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Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy

Abstract: Epigenetic regulation allows heritably modulating gene expression profiles without modifying the primary sequence of gDNA.

Cited by 95 publications

References 47 publications

HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma

Kaempferol Modulates DNA Methylation and Downregulates DNMT3B in Bladder Cancer

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