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

Çaçan, Ercan

doi:10.1002/cbin.10729

Cited by 32 publications

(26 citation statements)

References 42 publications

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“…We next wanted to examine the effects of selenite and MSA on tumor cells in more detail. Using western blotting, PDL1 expression was measured on the ovarian cancer cells, and in accordance with previous studies where A2780 expressed low levels of PDL1 ( 19 ), PDL1 was here below detection limit, while the cisplatin resistant CP70 cell line showed very high basal levels of PDL1. The PDL1 protein expression was significantly decreased upon treatment with selenite and MSA (Figure 3A ).…”

Section: Resultssupporting

confidence: 80%

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels

et al. 2018

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Redox active selenium (Se) compounds at sub toxic doses act as pro-oxidants with cytotoxic effects on tumor cells and are promising future chemotherapeutic agents. However, little is known about how Se compounds affect immune cells in the tumor microenvironment. We demonstrate that the inorganic Se compound selenite and the organic methylseleninic acid (MSA) do not, despite their pro-oxidant function, influence the viability of immune cells, at doses that gives cytotoxic effects in ovarian cancer cell lines. Treatment of the ovarian cancer cell line A2780 with selenite and MSA increases NK cell mediated lysis, and enhances the cytolytic activity of T cells. Increased T cell function was observed after incubation of T cells in preconditioned media from tumor cells treated with MSA, an effect that was coupled to decreased levels of PDL1, HIF-1α, and VEGF. In conclusion, redox active selenium compounds do not kill or inactivate immune cells at doses required for anti-cancer treatment, and we demonstrate that MSA enhances T cell-mediated tumor cell killing via PDL1 and VEGF inhibition.

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Section: Resultssupporting

confidence: 80%

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels

et al. 2018

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“…While the difference in mechanism of membrane-bound versus soluble PD-L1 has yet to be elucidated, we show here that total protein levels differ significantly from membrane-bound PD-L1 ligand. Others have shown that cisplatin-resistant cell lines have slightly higher PD-L1 surface expression than their parental cell lines 50 . We found that the Hey (cisplatin sensitive) and SKOV3 CR (cisplatin resistant) had the highest levels of PD-L1 by MFI (Fig.…”

Section: Discussionmentioning

confidence: 98%

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer

Moufarrij

Srivastava

Gomez

et al. 2020

Sci Rep

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Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53−/− ovarian cancer with HDAC6i/ DnMti led to an increase in tumor-killing cells such as ifng+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1 hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment. The five-year survival for ovarian cancer has remained unchanged for decades, and novel therapies are urgently needed 1. Ovarian cancer has the deadliest outcome among gynecologic cancers due to its late (typically Stage III or IV) presentation and aggressive phenotype. High-grade serous ovarian cancer, the most common subtype, is characterized by genomic instability with >95% of cases exhibiting mutations in the tumor suppressor P53 2. Treatment involves surgical staging and optimal debulking to reduce tumor burden, followed by chemotherapy with a platinum-based agent and a taxane, or vice versa (chemotherapy before surgery). Unfortunately most cancers recur within two years of chemotherapy. Significant advances in the pathobiology of the disease, including the identification of a subset of tumors with defects in homologous recombination (HR), have led to the use of PARP inhibitors, which can cause synthetic lethality in HR-deficient tumors. However, less than half of ovarian cancers are HR-deficient and there is no curative therapy for the majority of ovarian cancer patients 1,3. Cancer cells may be recognized as foreign by host immune cells that kill the cancer cells, but as they progress cancers exhibit mechanisms of immune evasion or immunoediting 4. The tumor microenvironment (TME) is composed of both pro-and anti-cancer immune cells. These include CD8 effector T cells that recognize specific antigens on tumor cells to kill them, natural killer (NK) cells, part of the innate immune system that can kill tumor cells, and immuno-suppressive cell types including macrophages, regulatory T cells, and myeloid-derived suppressor cells. Novel drugs that activate CD8 effector T cells to fight cancer cells, includ...

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“…Over the last decade, a large amount of evidence indicates that inflammation contributes to tumorigenesis. For example, transcription factors nuclear factor-κ B (NF-κB) and signal transducers and activators of transcription 3 (STAT3), two major pathways for inflammation, are activated by most cancer risk factors; an inflammatory condition precedes most cancers; NF-κ B and STAT3 are constitutively active in most cancers; hypoxia and acidic conditions found in solid tumors activate NF-κ B; chemotherapeutic agents and γ-irradiation activate NF-κ B and [112,113]. Many cancers result from chronic inflammation triggered by either extrinsic factors, [114] such as infection, autoimmunity, and tobacco smoke, or intrinsic factors, such as oncogene activatio [115].…”

Section: Immunosuppressive Mechanisms and Chronic Inflammationmentioning

confidence: 99%

Mechanism for the Decision of Ovarian Surface Epithelial Stem Cells to Undergo Neo-Oogenesis or Ovarian Tumorigenesis

Zheng

Hong

et al. 2018

Cell Physiol Biochem

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The ovary is surrounded by a whitish layer of mesodermally derived ovarian surface epithelium (OSE) that lines the intraembryonic celom and comprises simple squamous to cuboidal to low pseudostratified columnar epithelial cells. Its integrity is maintained by simple desmosomes, incomplete tight junctions, several integrins and cadherins. Recent research has found that ovarian stem cells (OSCs) exist within the OSE and may be responsible for both neo-oogenesis and ovarian cancer during adult life. The factors determining whether OSCs undergo neo-oogenesis or ovarian cancer are of great interest to researchers and clinicians. Accumulating evidence suggests the mechanism for the decision of ovarian surface epithelial stem cells to undergo either neo-oogenesis or ovarian cancer transformation may comprise both internal and external factors. Here, we review recent progress on how the internal factors, including genes, signaling pathways and lncRNA: OSE stem cells mediate the development and progression of ovarian cancer through various genes such as p53, KRAS, BRAF, and PTEN, and mutations in PIK3CA, and through various signaling pathways, including TGF-B pathway, Wnt signaling pathway, Notch signaling pathway, NF-kB signal transducer and transcriptional activator 3 (STAT3) pathway and Hedghog (HH) pathway. A series of expressions of IncRNA have changed in epithelial ovarian cancer tissues and cell lines compared to normal ovarian tissues and cell lines. As well as external factors, including incessant ovulation, gonadotropin and chronicinflammation: Frequent ovulation, without long-term dormancy, increases the risk of illness, because repeated rupture and repair at the ovulation site provides an opportunity for the accumulation of genetic aberrations; FSH affects all aspects of ovarian cancer metastasis, such as inhibition of apoptosis, through Induction of increased expression of VEGFA (VEGF) to support tumor growth, promote vascular growth, and possibly alter certain oncogenic pathways, thereby promoting proliferation and invasive phenotypic inflammation contributes to tumorigenesis, which help determine whether OSCs undergo neo-oogenesis or ovarian tumorigenesis. Understanding this issue is critical for developing novel strategies for premature ovarian failure and ovarian cancer prevention and therapy.

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

Cited by 32 publications

References 42 publications

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer

Mechanism for the Decision of Ovarian Surface Epithelial Stem Cells to Undergo Neo-Oogenesis or Ovarian Tumorigenesis

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