Epigenetic drugs as immunomodulators for combination therapies in solid tumors

Sigalotti, Luca; Fratta, Elisabetta; Coral, Sandra; Maio, Michele

doi:10.1016/j.pharmthera.2013.12.015

Cited by 94 publications

(88 citation statements)

References 134 publications

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“…The significant role of epigenetics in cancer immune escape provides a strong rationale for the use of epigenetic modifiers to improve immunologic targeting of neoplastic cells and to eventually design more effective cancer immunotherapies (11). Along this line, different epigenetic drugs that can revert epigenetic modifications are available, being currently used in the daily practice or in clinical trials (12)(13)(14)(15).…”

Section: (2)mentioning

confidence: 99%

“…Of relevance, long-lasting phenotypic immunomodulation appears to be essentially restricted to treatments with DNMTi through their ability to generate heritable changes in gene expression (23). The clinical appeal of these findings relays on the ability of the phenotypic modulations induced by epigenetic compounds to translate into an upregulated functional recognition and killing of tumor cells by antigen-specific CTL, both in vitro and in vivo (11,20). In addition, HDACi were found particularly effective in inducing a stress response on tumor cells, which led to the upregulated expression on their surface of the NKG2D ligands (MICA, MICB, and ULBPs) and to an increased killing of tumor cells by NK cells ( Fig.…”

Section: (2)mentioning

confidence: 99%

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Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy

Maio

Covre

Fratta

et al. 2015

Clinical Cancer Research

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Section: (2)mentioning

confidence: 99%

Section: (2)mentioning

confidence: 99%

Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy

Maio

Covre

Fratta

et al. 2015

Clinical Cancer Research

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“…2,3 Exposure of neoplastic cells to these agents effectively improved T cell recognition of melanoma and renal carcinoma cells in vitro. [3][4][5] This functional effect was found to be mediated, at least in part, by the upregulation of the expression of tumor antigens (e.g., Cancer Testis Antigens), HLA class I and accessory/co-stimulatory molecules by neoplastic cells.…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

et al. 2015

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The multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells; thus, we predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, the antitumor efficacy of the DNA hypomethylating agent 5-aza-2 0 -deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated. Murine mammary carcinoma TS/A or mesothelioma AB1 cells were injected in BALB/c, athymic nude, and SCID/Beige mice that were treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues. A significant antitumor effect of 5-AZA-CdR combined with mAb 9H10 was found: compared to controls, a 77% (p < 0.01), 54% (p < 0.01) and 33% (p D 0.2) decrease in TS/A tumor growth was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA-CdR or mAb 9H10, respectively. These antitumor activities were confirmed utilizing the AB1 model. 5-AZA-CdR-based regimens induced a promoter-demethylationsustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR. Antitumor efficacy of 5-AZA-CdR in athymic nude and SCID/Beige mice was not increased by mAb 9H10. In BALB/c mice, combined treatment induced the highest tumor infiltration by CD3 C lymphocytes, which included both CD8 C and CD4 C T cells; no such infiltrates were observed in normal tissues. This significant immune-related antitumor activity of 5-AZA-CdR combined with CTLA-4 blockade, demonstrated in highly aggressive mouse tumor models, provides a strong scientific rationale to implement epigenetically-based immunotherapies in cancer patients.

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“…As shown in Figure 4, TSA could affect many genes which had different functions, such as nucleic acid metabolism, transcription, immune, apoptosis, proliferation and ubiquitin. It indicated that TSA has diverse functions as other studies reported (Harrison and Dexter, 2013;Sigalotti et al, 2013). We focus on the genes associated with vital biological function, and did not report that their metylation alteration was related to NPC tumorigenesis before.…”

Section: Discussionmentioning

confidence: 99%

Effect of Trichostatin A on CNE2 Nasopharyngeal Carcinoma Cells - Genome-wide DNA Methylation Alteration

Yang

Zhang²,

Wu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Trichostatin A (TSA) is a histone deacetylase (HDAC) inhibitor. We here investigated its effects on proliferation and apoptosis of the CNE2 carcinoma cell line, and attempted to establish genome-wide DNA methylation alteration due to differentially histone acetylation status. After cells were treated by TSA, the inhibitory rate of cell proliferation was examined with a CCK8 kit, and cell apoptosis was determined by flow cytometry. Compared to control, TSA inhibited CNE2 cell growth and induced apoptosis. Furthermore, TSA was found to induce genome-wide methylation alteration as assessed by genome-wide methylation array. Overall DNA methylation level of cells treated with TSA was higher than in controls. Function and pathway analysis revealed that many genes with methylation alteration were involved in key biological roles, such as apoptosis and cell proliferation. Three genes (DAP3, HSPB1 and CLDN) were independently confirmed by quantitative real-time PCR. Finally, we conclude that TSA inhibits CNE2 cell growth and induces apoptosis in vitro involving genome-wide DNA methylation alteration, so that it has promising application prospects in treatment of NPC in vivo. Although many unreported hypermethylated/hypomethylated genes should be further analyzed and validated, the pointers to new biomarkers and therapeutic strategies in the treatment of NPC should be stressed.

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Epigenetic drugs as immunomodulators for combination therapies in solid tumors

Cited by 94 publications

References 134 publications

Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy

Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

Effect of Trichostatin A on CNE2 Nasopharyngeal Carcinoma Cells - Genome-wide DNA Methylation Alteration

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