5-Azacytidine Potentiates Anti-tumor Immunity in a Model of Pancreatic Ductal Adenocarcinoma

Ebelt, Nancy D.; Zuniga, Edith; Johnson, B. Lamar; Diamond, Don J.; Manuel, Edwin R.

doi:10.3389/fimmu.2020.00538

Cited by 19 publications

(11 citation statements)

References 61 publications

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“…However, recent studies revealed that DNA demethylation increase tumor antigen and reactivate endogenous retroviral sequences [ 39 , 40 ]. In terms of relationship to immune checkpoint inhibitor, the DNMT inhibitor 5-azacytidine inhibits immune evasion in cancer through up-regulation of tumor antigen presentation and T-cell chemokine expression [ 41 , 42 ]. Interestingly, decitabine improve the effectiveness of immune checkpoint inhibitor via modulation of stroma-rich tumor microenvironment by inducing STAT1 and IFN-γ signaling [ 43 , 44 ].…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy

2022

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Pancreatic adenocarcinoma is a lethal cancer with poor response to chemotherapy and immune checkpoint inhibitors. Recent studies suggest that epigenetic alterations contribute to its aggressive biology and the tumor microenvironment which render it unresponsive to immune checkpoint blockade. Here, we review our current understandings of epigenetic dysregulation in pancreatic adenocarcinoma, its effect on the tumor immune microenvironment, and the potential for epigenetic therapy to be combined with immune checkpoint inhibitors.

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Section: Dna Methylationmentioning

confidence: 99%

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy

2022

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“…Further supporting the utility of DNMT inhibition in PDAC TME reprogramming, DNMT blockade in immunocompetent PDAC models enhanced CD4 + and CD8 + T-cell infiltration and caused significant tumor regression (Fig. 2) [37]. However, in contrast to these findings, pharmacological or genetic depletion of DNMT1 resulted in increased production of hyaluronic acid, thus promoting PDAC progression (Fig.…”

Section: Targeting Epigenetics To Interfere With Cellular Pdac Heterogeneitymentioning

confidence: 72%

Epigenetic Therapeutic Strategies to Target Molecular and Cellular Heterogeneity in Pancreatic Cancer

Versemann¹,

Heßmann²,

Ulisse³

2021

Visc Med

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Background: Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <10%. Compelling evidence suggests that the devastating disease outcome of PDAC patients is linked to a high degree of intra- and interindividual tumor heterogeneity, which is predominantly installed at the level of gene transcription. The cellular and molecular complexities of the disease explain the poor efficacy of “one-size-fits-all” therapeutic approaches in PDAC treatment and strongly argue for pursuing tailored therapeutic strategies to tackle PDAC. In a highly dynamic manner, a network of transcription factors and epigenetic regulatory proteins temporally and spatially control the diverse transcriptomic states determining PDAC heterogeneity. Given the reversibility of epigenetic processes, pharmacological intervention with key epigenetic drivers of PDAC heterogeneity appeals as a promising concept to shift the transcriptomic phenotype of PDAC toward a less aggressive and more chemosensible state. Summary: In this review, we discuss the chances and pitfalls of epigenetic treatment strategies in overcoming and shifting molecular and cellular PDAC heterogeneities in order to combat PDAC. To this end, we utilized the keywords “pancreatic cancer,” “heterogeneity,” and “epigenetics” to search for relevant articles on the database PubMed and selected interventional studies enrolling PDAC patients as displayed in clinicaltrails.gov to generate a synopsis of clinical trials involving epigenetic targeting. Key Messages: Targeting epigenetic regulators in PDAC represents a promising concept to reprogram molecular and cellular tumor heterogeneities in the pancreas and hence to modulate the PDAC phenotype in favor of a less aggressive and more therapy susceptible disease course. However, we just start to understand the complex interactions of epigenetic regulators in controlling PDAC plasticity, and a clinical breakthrough utilizing epigenetic targeting in PDAC patients has not been achieved yet. Nevertheless, increasing translational efforts which consider the pleiotropic effects of targeting epigenetic regulation in different cellular compartments of the tumor and that focus on the utility and sequence of combinatory treatment approaches might pave the way toward novel epigenetic treatment strategies in PDAC therapy.

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“…Transposable elements and tumor-associated antigens are potentially highly immunogenic. These are upregulated during the transition from a premalignant state to malignancy in a murine PDAC model, which coincides with a downregulation of antigen presentation and T cell recruitment, signifying immune evasion of tumor [116]. By treating mice with the DNA methyltransferase inhibitor 5-azacytidine, tumor regression was observed in immunocompetent mice, indicating that the immune system controlled tumor growth, with the epigenetic treatment enhancing tumor immunogenicity.…”

Section: Immune Therapymentioning

confidence: 97%

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

Roalsø

Hald

Alexeeva

et al. 2022

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to modulate and possibly enhance immune-based treatments. Epigenetic marks can also serve as diagnostic screening tools, as epigenetic changes occur at early stages of the disease. Further, epigenetics can be used in prognostication. The field is evolving, and this review seeks to provide an updated overview of the emerging role of epigenetics in the diagnosis, treatment, and prognostication of PDAC.

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5-Azacytidine Potentiates Anti-tumor Immunity in a Model of Pancreatic Ductal Adenocarcinoma

Cited by 19 publications

References 61 publications

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy

Epigenetic Therapeutic Strategies to Target Molecular and Cellular Heterogeneity in Pancreatic Cancer

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

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