Immunological effects of hypomethylating agents

Lindblad, Katherine E.; Goswami, Mousumi; Hourigan, Christopher S.; Oetjen, Karolyn A.

doi:10.1080/17474086.2017.1346470

Cited by 48 publications

(54 citation statements)

References 73 publications

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“…High-dose decitabine is known to display cytotoxic effects. Recently, researchers have found that there was no correlation between methylation reversal of tumor suppressor genes and clinical response in some patients treated with decitabine, implying that demethylation drugs might have other unidentified mechanisms that need to be elucidated ( 49 , 50 ). The results of our study showed that Fer-1, DFO, necrostatin-1, and the former that has the most significant effect could reverse the growth-inhibitory effect of decitabine on SKM-1 and MUTZ-1, indicating that ferroptosis and necroptosis may be the main mechanisms of decitabine-induced cell death of MDS cells.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Ferroptosis in Myelodysplastic Syndrome

Niu

Yue

et al. 2020

Front. Oncol.

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Background Ferroptosis is a form of iron-dependent non-apoptotic cell death, with characteristics of loss of the activity of the lipid repair enzyme, glutathione (GSH) peroxidase 4 (GPX4), and accumulation of lethal reactive lipid oxygen species. The mechanism of ferroptosis in myelodysplastic syndrome (MDS) is unclear. Methods Cell viability assay, reactive oxygen species (ROS) assay, GSH assay, and GPX activity assay were performed to study the regulation of ferroptosis in MDS cells obtained from MDS patients, the iron overload model mice, and cell lines. Results The growth-inhibitory effect of decitabine could be partially reversed by ferrostatin-1 and iron-chelating agent [desferrioxamine (DFO)] in MDS cell lines. Erastin could increase the cytotoxicity of decitabine on MDS cells. The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1. The concentration of hemoglobin in peripheral blood of iron overload mice was negatively correlated with intracellular Fe 2+ level and ferritin concentration. Iron overload (IO) led to decreased viability of bone marrow mononuclear cells (BMMNCs), which was negatively correlated with intracellular Fe 2+ level. Ferrostatin-1 partially reversed the decline of cell viability in IO groups. The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in BMMNCs of IO mice. DFO could increase the level of GSH. Ferrostatin-1 and DFO could increase the GPX4 activity of BMMNCs in IO mice. Ferrostatin-1 could significantly reverse the growth-inhibitory effect of decitabine in MDS patients. Decitabine could significantly increase the ROS level in MDS groups, which could be inhibited by ferrostatin-1 or promoted by erastin. Ferrostatin-1 could significantly reverse the inhibitory effect of decitabine on GSH levels in MDS patients. Erastin combined with decitabine could further reduce the GSH level. Erastin could further decrease the activity of GPX4 compared with the decitabine group. Conclusion Ferroptosis may account for the main mechanisms of how decitabine induced death of MDS cells. Decitabine-induced ROS raise leads to ferroptosis in MDS cells by decreasing GSH level and GPX4 activity.

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Section: Discussionmentioning

confidence: 99%

Abnormal Ferroptosis in Myelodysplastic Syndrome

Niu

Yue

et al. 2020

Front. Oncol.

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“…Epigenetic-targeting agents, particularly DNA methyltransferase inhibitors (DNMTIs), are being investigated in combination with anti-PD1 therapy in hematologic malignancies (2). Enhanced endogenous retroviral expression and cancer testis antigen expression induced by demethylation results in increased tumor recognition by immune cells (3)(4)(5)(6)(7). We have previously shown that ascorbic acid (AA) causes demethylation and corresponding increase in the hydroxymethylation fraction of both lymphoma and renal cell carcinoma cells by enhancing the activity of the Ten-Eleven Translocation (TET) enzymes (8,9).…”

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confidence: 99%

“…We hypothesized that AA may be an optimal demethylating agent for combination with anti-PD1 therapy as it has also been shown to enhance the function of immune cells such as natural killer (NK) cells, macrophages, and dendritic cells (11,12). In contrast, effects of DNMTIs on immune cells are inconsistent, with some studies indicating an inhibitory effect (3,(13)(14)(15)(16). Importantly, high-dose AA has been shown to be a promising anticancer agent in early-phase clinical trials and is not only well tolerated but appears to decrease the side effects of chemotherapy (17).…”

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confidence: 99%

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

Luchtel

Bhagat

Pradhan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

113

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Major efforts are underway to identify agents that can potentiate effects of immune checkpoint inhibition. Here, we show that ascorbic acid (AA) treatment caused genomewide demethylation and enhanced expression of endogenous retroviral elements in lymphoma cells. AA also increased 5-hydroxymethylcytosine (5hmC) levels of CD8+ T cells and enhanced their cytotoxic activity in a lymphoma coculture system. High-dose AA treatment synergized with anti-PD1 therapy in a syngeneic lymphoma mouse model, resulting in marked inhibition of tumor growth compared with either agent alone. Analysis of the intratumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intratumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intratumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and natural killer cells), and interleukin 12 production by antigen-presenting cells compared with single-agent anti-PD1. These data indicate that AA potentiates anti-PD1 checkpoint inhibition through synergistic mechanisms. The study provides compelling rationale for testing combinations of high-dose AA and anti-PD1 agents in patients with aggressive B cell lymphoma as well as in preclinical models of other malignancies.

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“…The downregulation or loss of MHC expression, the genetic loss or silencing of antigen source protein are well-known immune escape mechanisms in cancer. This can be fairly extensive as described in haplo-identical transplants, where the loss of the entire mismatched haplotype can be observed (152). Elaborate strategies targeting MHC-associated peptides presented by different alleles and belonging to different haplotypes may be necessary to harness the therapeutic potential of T-cell immunotherapy against genetic variants translated into MHC-associated peptides.…”

Section: Perspectives and Clinical Integration Of T-cell Therapiesmentioning

confidence: 99%

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies

et al. 2020

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Over the last decades, T-cell immunotherapy has revealed itself as a powerful, and often curative, strategy to treat blood cancers. In hematopoietic cell transplantation, most of the so-called graft-vs.-leukemia (GVL) effect hinges on the recognition of histocompatibility antigens that reflect immunologically relevant genetic variants between donors and recipients. Whether other variants acquired during the neoplastic transformation, or the aberrant expression of gene products can yield antigenic targets of similar relevance as the minor histocompatibility antigens is actively being pursued. Modern genomics and proteomics have enabled the high throughput identification of candidate antigens for immunotherapy in both autologous and allogeneic settings. As such, these major histocompatibility complex-associated tumor-specific (TSA) and tumor-associated antigens (TAA) can allow for the targeting of multiple blood neoplasms, which is a limitation for other immunotherapeutic approaches, such as chimeric antigen receptor (CAR)-modified T cells. We review the current strategies taken to translate these discoveries into T-cell therapies and propose how these could be introduced in clinical practice. Specifically, we discuss the criteria that are used to select the antigens with the greatest therapeutic value and we review the various T-cell manufacturing approaches in place to either expand antigen-specific T cells from the native repertoire or genetically engineer T cells with minor histocompatibility antigen or TSA/TAA-specific recombinant T-cell receptors. Finally, we elaborate on the current and future incorporation of these therapeutic T-cell products into the treatment of hematological malignancies.

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Immunological effects of hypomethylating agents

Cited by 48 publications

References 73 publications

Abnormal Ferroptosis in Myelodysplastic Syndrome

Abnormal Ferroptosis in Myelodysplastic Syndrome

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies

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