Radiation-induced modulation of immunogenic genes in tumor cells is regulated by both histone deacetylases and DNA methyltransferases

Çaçan, Ercan; Greer, Susanna F.; Garnett-Benson, Charlie

doi:10.3892/ijo.2015.3192

Cited by 14 publications

(15 citation statements)

References 74 publications

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“…Demethylation of the foxp3 locus yields the gene accessible to the binding of numerous transcription factors [62]. Radiation can alter the epigenetic enzymes associated with specific gene promotors in cancer cells [63,64] and has been reported to alter DNA methylation, both globally and in a gene-specific manner [65]. Thus, it seems reasonable that radiation could be altering the epigenetic state of the foxp3 locus, and we would expect iT REGS to be more sensitive to these changes since the region is already partially methylated.…”

Section: Discussionmentioning

confidence: 99%

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

2020

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Background: The use of immunotherapy strategies for the treatment of advanced cancer is rapidly increasing. Most immunotherapies rely on induction of CD8+ tumor-specific cytotoxic T cells that are capable of directly killing cancer cells. Tumors, however, utilize a variety of mechanisms that can suppress anti-tumor immunity. CD4+ regulatory T cells can directly inhibit cytotoxic T cell activity and these cells can be recruited, or induced, by cancer cells allowing escape from immune attack. The use of ionizing radiation as a treatment for cancer has been shown to enhance anti-tumor immunity by several mechanisms including immunogenic tumor cell death and phenotypic modulation of tumor cells. Less is known about the impact of radiation directly on suppressive regulatory T cells. In this study we investigate the direct effect of radiation on human T REG viability, phenotype, and suppressive activity. Results: Both natural and TGF-β1-induced CD4+ T REG cells exhibited increased resistance to radiation (10 Gy) as compared to CD4+ conventional T cells. Treatment, however, decreased Foxp3 expression in natural and induced T REG cells and the reduction was more robust in induced T REGS. Radiation also modulated the expression of signature iT REG molecules, inducing increased expression of LAG-3 and decreased expression of CD25 and CTLA-4. Despite the disconcordant modulation of suppressive molecules, irradiated iT REGS exhibited a reduced capacity to suppress the proliferation of CD8+ T cells. Conclusions: Our findings demonstrate that while human T REG cells are more resistant to radiation-induced death, treatment causes downregulation of Foxp3 expression, as well as modulation in the expression of T REG signature molecules associated with suppressive activity. Functionally, irradiated TGF-β1-induced T REGS were less effective at inhibiting CD8+ T cell proliferation. These data suggest that doses of radiotherapy in the hypofractionated range could be utilized to effectively target and reduce T REG activity, particularly when used in combination with cancer immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

2020

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“…More recently, we have reported that radiation (5 Gy) similarly increases histone acetylation at both the Fas and DR5 promoters in addition to the 4-1BBL promoter. Further, less HDAC2, HDAC3 and DNMT1 were bound to the promoter regions of both 4-1BBL and Fas, but not other genes following IR of human tumor cells [77]. These observations suggest that radiation can also regulate the expression of specific genes by epigenetic mechanisms.…”

Section: Epigeneticmentioning

confidence: 79%

Immunomodulatory Effects of Radiation: What is Next for Cancer Therapy?

et al. 2015

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Despite its former reputation as being immunosuppressive, it has become evident that radiation therapy can enhance antitumor immune responses. This quality can be harnessed by utilizing radiation as an adjuvant to cancer immunotherapies. Most studies combine the standard radiation dose and regimens indicated for the given disease state, with novel cancer immunotherapies. It has become apparent that low-dose radiation, as well as doses within the hypofractionated range, can modulate tumor cells making them better targets for immune cell reactivity. Herein, we describe the range of phenotypic changes induced in tumor cells by radiation, and explore the diverse mechanisms of immunogenic modulation reported at these doses. We also review the impact of these doses on the immune cell function of cytotoxic cells in vivo and in vitro.

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“…DNMTs are responsible for methylating DNA and for silencing genes. We have recently observed that 4‐1BBL expression is regulated by DNA methylation in colorectal cancer cells (Cacan et al, ). However, it is unclear if suppression of 4‐1BBL and OX‐40L are regulated by DNA methylation in chemoresistant ovarian cancer cells.…”

Section: Resultsmentioning

confidence: 99%

“…Recruitment of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) to the promoter region of a gene suppresses its transcriptional activity. It has been shown that expression of OX‐40L and 4‐1BBL can be influenced by DNA methylation and histone acetylation in colorectal cancer (Cacan et al, ). Thus, epigenetic regulation of costimulatory molecules may also contribute to their dynamic expressions in cancer progression; however, the molecular details about epigenetic regulation of these costimulatory molecules in chemoresistant ovarian cancer cells remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic‐mediated immune suppression of positive co‐stimulatory molecules in chemoresistant ovarian cancer cells

Çaçan

2017

Cell Biology International

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The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4-1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4-1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells.

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Radiation-induced modulation of immunogenic genes in tumor cells is regulated by both histone deacetylases and DNA methyltransferases

Cited by 14 publications

References 74 publications

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

Immunomodulatory Effects of Radiation: What is Next for Cancer Therapy?

Epigenetic‐mediated immune suppression of positive co‐stimulatory molecules in chemoresistant ovarian cancer cells

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