High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model
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PROVIDER: PRJNA593266 | ENA |
REPOSITORIES: ENA
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Project description:High-dose Ascorbic acid synergizes with anti-PD1 in a Lymphoma mouse model
| PRJNA593511 | ENA
Project description:Major efforts are underway to identify agents that can potentiate effects of immune checkpoint inhibition. Here, we show that ascorbic acid (AA) treatment caused genome wide 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 co-culture 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 intra-tumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intra-tumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intra-tumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and Natural Killer cells), and IL-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 AA and anti-PD1 agents in lymphoma patients as well as in pre-clinical models of other malignancies.
2020-01-27 | GSE141444 | GEO
Project description:Major efforts are underway to identify agents that can potentiate effects of immune checkpoint inhibition. Here, we show that ascorbic acid (AA) treatment caused genome wide 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 co-culture 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 intra-tumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intra-tumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intra-tumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and Natural Killer cells), and IL-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 AA and anti-PD1 agents in lymphoma patients as well as in pre-clinical models of other malignancies.
2020-01-27 | GSE141397 | GEO
Project description: Not available
| S-EPMC6983418 | biostudies-literature
Project description:Background: Clear guidelines for therapy of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-a monotherapy and high-dose ascorbic acid (AA) monotherapy in open clinical trials. However, there is no clear evidence to support the value of one of these specific treatment approaches, due to the lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-a treatment in the context of HAM/TSP. Principal Findings: Based on flow cytometry and thymidine incorporation, we demonstrated for the first time that high-dose AA displays superior antiproliferative and immunomodulatory effects over IFN-a in HAM/TSP PBMCs ex vivo. In addition, high-dose AA induces cell death in HTLV-1-infected T-cell lines in vitro. Microarray combined with Ingenuity Pathway Analysis revealed AA-induced modulation of genes associated with cell death and cell cycle. Conclusions: In comparison with IFN-a, high-dose AA is preferred as anti-HTLV-1 treatment in vitro, due to its superior cell death-inducing, antiproliferative and immunomodulatory effects. Considering the lack of treatment options, the mild in vivo side effects and the low cost price, high-dose AA should be further explored for its therapeutic potential in HAM/TSP treatment. In total, 15 samples were analyzed. One microarray experiment was performed, including triplicate samples for each treatment condition (untreated, IFN-a, 10 µg/ml ascorbic acid, 50 µg/ml ascorbic acid, 100 µg/ml ascorbic acid). Triplicate samples were obtained from three separate RNA experiments.
2012-06-13 | E-GEOD-34572 | biostudies-arrayexpress
Project description:Background: Clear guidelines for therapy of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-a monotherapy and high-dose ascorbic acid (AA) monotherapy in open clinical trials. However, there is no clear evidence to support the value of one of these specific treatment approaches, due to the lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-a treatment in the context of HAM/TSP. Principal Findings: Based on flow cytometry and thymidine incorporation, we demonstrated for the first time that high-dose AA displays superior antiproliferative and immunomodulatory effects over IFN-a in HAM/TSP PBMCs ex vivo. In addition, high-dose AA induces cell death in HTLV-1-infected T-cell lines in vitro. Microarray combined with Ingenuity Pathway Analysis revealed AA-induced modulation of genes associated with cell death and cell cycle. Conclusions: In comparison with IFN-a, high-dose AA is preferred as anti-HTLV-1 treatment in vitro, due to its superior cell death-inducing, antiproliferative and immunomodulatory effects. Considering the lack of treatment options, the mild in vivo side effects and the low cost price, high-dose AA should be further explored for its therapeutic potential in HAM/TSP treatment.
2012-06-14 | GSE34572 | GEO
Project description:Recent success in cancer immunotherapy has come from the blockade of inhibitory receptors on T cells, such as programmed cell death-1, which can induce a state of T cell exhaustion upon constant antigen stimulation. Understanding miRNA regulation of PD1 can be useful to discover miRNAs for use in therapy or as prognostic markers in various diseases including cancer, autoimmunity and transplantation. We used microarrays to discover global miRNA expression changes upon PD1 upregulation and identified miRNAs that are both up- and down-regulated. B16F10 cells were injected subcutaneously into C57BL/6 mice and 16 days later CD4+PD1+ and CD4+PD1- were sorted from the lymph nodes and spleen for RNA extraction and hybridization on Affymetrix miRNA array.
2015-08-01 | E-GEOD-65208 | biostudies-arrayexpress
Project description:Transcriptome comparison of the Streptococcus pneumoniae D39 wild-type grown in M17 medium to grown in M17 medium + 10mM ascorbic acid (AM17).
2015-01-21 | GSE64105 | GEO
Project description:Effect of Ascorbic acid on human genome
2009-10-15 | E-MEXP-1861 | biostudies-arrayexpress
Project description:In addition to the role of antioxidant, ascorbic acid (reducing Vitamin C) is an important cofactor for Fe2+ and α-ketoglutarate (α-KG) dependent dioxygenases (Fe2+/α-KGDDs) that comprise many diverse enzymes, including collagen prolyl hydroxylases, jmjC (Jumonji C) domain containing histone demethylases, Ten-eleven translocation (TET) 5-methyl cytosine (5mC) dioxygenases, and N6-methyl adenosine (m6A) demethylase FTO and ALKBH5. Ascorbic acid was reported to induce global epigenetic reprogramming. Here we optimized the library construction flow chart of single-stranded DNA profiling method KAS-seq and utilized KAS-seq to profile transient chromatin states changes upon ascorbic acid treatment for 10 min. We identified several critical pathways affected by ascorbic acid treatment, providing some clues for explaining the reported positive impact of anti-cancer, anti-depression, and anti-obesity for taking ascorbic acid.
2023-07-25 | GSE237843 | GEO