Epigenetic Modifiers in Immunotherapy: a Focus on Checkpoint Inhibitors

Terranova-Barberio, Manuela; Thomas, Scott; Münster, Pamela N.

doi:10.2217/imt-2016-0014

Cited by 62 publications

(44 citation statements)

References 127 publications

(129 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This study also reported that mice treated with PD-L1 checkpoint blockade or DZNep (an inhibitor of all SAM-dependent enzymes) plus DAC exerted a decreased tumor size, increased CD8+ T lymphocytes and Th1-type chemokine expression [27]. Therefore, the inhibition of DNA hypermethylation synergistically increases the therapeutic efficacy of anti-PD-L1 therapy [117]. To evaluate the correlation of immune checkpoints (PD-L1, PD-L2, PD-1 and CTLA-4) with DNMTi in patients with myeloid malignancies, a study evaluated the effect of the treatment of leukemia cells with DAC and revealed that DAC leads to a dosedependent upregulation of these 4 genes [118].…”

Section: Dnmti Boosts Tumor Immune Checkpoint Markermentioning

confidence: 67%

Clinical significance of promoter hypermethylation of genes in ovarian cancer

Zhu¹,

Lang²

2017

Oncotarget

View full text Add to dashboard Cite

Ovarian cancer is the most lethal condition in gynecologic oncology. The known prognostic factors for ovarian cancer include tumor stage, histological grade, lymph node, and distant metastasis; however, handy and reliable molecular biomarkers for prevention, diagnosis, personalized treatment, and prognosis are scarce. Despite histological differences, the clinical treatment strategy is similar for ovarian cancers. The survival rate for ovarian cancer, however, remains relatively low. Accumulating evidence suggests that hypermethylated promoters of genes can be promising candidates as molecular biomarkers in ovarian cancer risk evaluation, early detection, personalized treatment, and prognosis. With advancements in immunology, hypermethylation of gene promoters was found to alter the tumor immune microenvironment, and gene methyltransferase inhibitors can contribute to ovarian cancer immunotherapy by boosting tumor immunogenicity and immune response and decreasing immunosuppression. Although DNMTis demonstrate high efficacy in hematologic malignancies, the application of DNMTis in solid tumors is just in its beginning. This article, drawing on both preclinical and clinical data, systematically reviews the common hypermethylated genes in ovarian cancer and their clinical applications, evaluating their usefulness in early diagnosis, personalized treatment, prognosis prediction, and the establishment of combined therapy of methyltransferase inhibitors and immunotherapy.www.impactjournals.com/oncotarget/

show abstract

Section: Dnmti Boosts Tumor Immune Checkpoint Markermentioning

confidence: 67%

Clinical significance of promoter hypermethylation of genes in ovarian cancer

Zhu¹,

Lang²

2017

Oncotarget

View full text Add to dashboard Cite

show abstract

“…In addition to the initiation of ICD, the ability of conventional chemotherapies to upregulate MHC classes I and II enables malignant cells to be better recognized and destroyed by the immune system [43,44]. Tumor-Associated Antigens (TAAs) are presented on MHC class I to CD8 + cytolytic T cells, which can then directly eliminate cancer [45].…”

Section: Impact Of Chemotherapy On Anti-tumor Immunity and Cancer mentioning

confidence: 99%

“…Not surprisingly, HDACi can modify the expression of inhibitory molecules (Figure 3) [44]. For example, class I HDACi were demonstrated to upregulate PD-L1/L2 surface protein and RNA transcription in melanoma patients, in melanoma cell lines and in a syngeneic mouse model of melanoma, through acetylation of the PD-L1 and PD-L2 promotor [164].…”

Section: Impact Of Epigenetic Modifiers On Anti-tumor Immunity Camentioning

confidence: 99%

“…DNA methylation acts to repress gene transcription and is involved in the regulation of human leukocyte antigens, and MHC class I downregulation in cancer is associated with promoter hypermethylation [48,169]. Hence, administration of DNMTi can reverse chronic MHC class I suppression found in many malignancies [44]. Azacitidine, for example, potentiated MHC class I surface expression in vitro and in vivo in murine lung carcinoma by increasing the transcription of antigen-presenting genes including TAP-1, TAP-2, LMP-2, LMP-7 and tapasin [170,171,172].…”

Section: Impact Of Epigenetic Modifiers On Anti-tumor Immunity Camentioning

confidence: 99%

See 1 more Smart Citation

The Impact of Chemotherapy, Radiation and Epigenetic Modifiers in Cancer Cell Expression of Immune Inhibitory and Stimulatory Molecules and Anti-Tumor Efficacy

2016

View full text Add to dashboard Cite

Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules.

show abstract

“…Predominant responses to HDACi generally include inhibition of proliferation and induction of cell death, which is linked to efficacy in experimental models, and tumor cell "intrinsic" responses may include modulating tumor immunogenicity (12), priming the immune response by increasing expression of tumorassociated antigens and immune-regulated genes, as well as modulating chemokines and cytokines involved in immune system activation (13,14). It has also become clear that effects of HDACis are highly dependent upon context and not easily anticipated.…”

mentioning

confidence: 99%

Histone deacetylase inhibitors as cancer therapeutics

Clawson¹

2016

Ann. Transl. Med.

View full text Add to dashboard Cite

Cancer cells contain significant alterations in their epigenomic landscape, which several enzyme families reversibly contribute to. One class of epigenetic modifying enzymes is that of histone deacetylases (HDAC), which are receiving considerable scrutiny clinically as a therapeutic target in many cancers. The underlying rationale is that inhibiting HDACs will reverse dysregulated target gene expression by modulating functional histone (or other) acetylation marks. This perspective will discuss a recent paper by Markozashvili and co-workers which appeared in Gene, which indicates that the mechanisms by which HDAC inhibitors (HDACis) alter the epigenetic landscape include widespread alternative effects beyond simply controlling regional epigenetic marks.HDACs are involved in many processes/diseases, and it is not surprising that HDACis have considerable off-target effects, and thus a major effort is being directed toward identification of inhibitors which are selective for HDAC isoforms often uniquely implicated in various cancers. This Perspective will also discuss some representative work with inhibitors targeting individual HDAC classes or isoforms. At present, it is not really clear that isoform-specific HDACis will avoid non-selective effects on other unrecognized activities of HDACs.

show abstract

Epigenetic Modifiers in Immunotherapy: a Focus on Checkpoint Inhibitors

Cited by 62 publications

References 127 publications

Clinical significance of promoter hypermethylation of genes in ovarian cancer

Clinical significance of promoter hypermethylation of genes in ovarian cancer

The Impact of Chemotherapy, Radiation and Epigenetic Modifiers in Cancer Cell Expression of Immune Inhibitory and Stimulatory Molecules and Anti-Tumor Efficacy

Histone deacetylase inhibitors as cancer therapeutics

Contact Info

Product

Resources

About