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Combined treatment with epigenetic agents enhances anti-tumor activity of MAGE-D4 peptide-specific T cells by upregulating the MAGE-D4 expression in glioma
OBJECTIVE: The study evaluated the efficacy of combined epigenetic drugs of decitabine (DAC), valproic acid (VPA), and trichostatin A (TSA) on immunotherapy against glioma. METHODS: The expression and prognosis of MAGE-D4 in glioma were analyzed online, and the expression of MAGE-D4 and HLA-A2 in gl...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9382192/ https://www.ncbi.nlm.nih.gov/pubmed/35992806 http://dx.doi.org/10.3389/fonc.2022.873639 |
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author | Bi, Shui-Qing Zhang, Qing-Mei Zeng, Xia Liu, Chang Nong, Wei-Xia Xie, Huan Li, Feng Lin, Li-Na Luo, Bin Ge, Ying-Ying Xie, Xiao-Xun |
author_facet | Bi, Shui-Qing Zhang, Qing-Mei Zeng, Xia Liu, Chang Nong, Wei-Xia Xie, Huan Li, Feng Lin, Li-Na Luo, Bin Ge, Ying-Ying Xie, Xiao-Xun |
author_sort | Bi, Shui-Qing |
collection | PubMed |
description | OBJECTIVE: The study evaluated the efficacy of combined epigenetic drugs of decitabine (DAC), valproic acid (VPA), and trichostatin A (TSA) on immunotherapy against glioma. METHODS: The expression and prognosis of MAGE-D4 in glioma were analyzed online, and the expression of MAGE-D4 and HLA-A2 in glioma induced by epigenetic drugs was detected by qRT-PCR, Western blot, and flow cytometry. The methylation status of the MAGE-D4 promoter was determined by pyrosequencing. An HLA-A2 restricted MAGE-D4 peptide was predicted and synthesized. An affinity assay and a peptide/HLA complex stability assay were performed to determine the affinity between peptide and HLA. CCK8 assay, CFSE assay, ELISA and ELISPOT were performed to detect the function of MAGE-D4 peptide-specific T cells. Flow cytometry, ELISA, and cytotoxicity assays were used to detect the cytotoxicity effect of MAGE-D4 peptide-specific T cells combined with epigenetic drugs against glioma in vitro. Finally, the glioma-loaded mouse model was applied to test the inhibitory effect of specific T cells on gliomas in vivo. RESULTS: MAGE-D4 was highly expressed in glioma and correlated with poor prognosis. Glioma cells could be induced to express MAGE-D4 and HLA-A2 by epigenetic drugs. MAGE-D4-associated peptides were found that induce DCs to stimulate the highest T-cell activities of proliferation, IL-2 excretion, and IFN-γ secretion. MAGE-D4 peptide-specific T cells treated with TSA only or combining TSA and DAC had the most cytotoxicity effect, and its cytotoxicity effect on glioma cells decreased significantly after HLA blocking. In vivo experiments also confirmed that MAGE-D4-specific T cells inhibit TSA-treated glioma. CONCLUSION: MAGE-D4 is highly expressed in glioma and correlated with the prognosis of glioma. The novel MAGE-D4 peptide identified was capable of inducing MAGE-D4-specific T cells that can effectively inhibit glioma growth, and the epigenetic drug application can enhance this inhibition. |
format | Online Article Text |
id | pubmed-9382192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93821922022-08-18 Combined treatment with epigenetic agents enhances anti-tumor activity of MAGE-D4 peptide-specific T cells by upregulating the MAGE-D4 expression in glioma Bi, Shui-Qing Zhang, Qing-Mei Zeng, Xia Liu, Chang Nong, Wei-Xia Xie, Huan Li, Feng Lin, Li-Na Luo, Bin Ge, Ying-Ying Xie, Xiao-Xun Front Oncol Oncology OBJECTIVE: The study evaluated the efficacy of combined epigenetic drugs of decitabine (DAC), valproic acid (VPA), and trichostatin A (TSA) on immunotherapy against glioma. METHODS: The expression and prognosis of MAGE-D4 in glioma were analyzed online, and the expression of MAGE-D4 and HLA-A2 in glioma induced by epigenetic drugs was detected by qRT-PCR, Western blot, and flow cytometry. The methylation status of the MAGE-D4 promoter was determined by pyrosequencing. An HLA-A2 restricted MAGE-D4 peptide was predicted and synthesized. An affinity assay and a peptide/HLA complex stability assay were performed to determine the affinity between peptide and HLA. CCK8 assay, CFSE assay, ELISA and ELISPOT were performed to detect the function of MAGE-D4 peptide-specific T cells. Flow cytometry, ELISA, and cytotoxicity assays were used to detect the cytotoxicity effect of MAGE-D4 peptide-specific T cells combined with epigenetic drugs against glioma in vitro. Finally, the glioma-loaded mouse model was applied to test the inhibitory effect of specific T cells on gliomas in vivo. RESULTS: MAGE-D4 was highly expressed in glioma and correlated with poor prognosis. Glioma cells could be induced to express MAGE-D4 and HLA-A2 by epigenetic drugs. MAGE-D4-associated peptides were found that induce DCs to stimulate the highest T-cell activities of proliferation, IL-2 excretion, and IFN-γ secretion. MAGE-D4 peptide-specific T cells treated with TSA only or combining TSA and DAC had the most cytotoxicity effect, and its cytotoxicity effect on glioma cells decreased significantly after HLA blocking. In vivo experiments also confirmed that MAGE-D4-specific T cells inhibit TSA-treated glioma. CONCLUSION: MAGE-D4 is highly expressed in glioma and correlated with the prognosis of glioma. The novel MAGE-D4 peptide identified was capable of inducing MAGE-D4-specific T cells that can effectively inhibit glioma growth, and the epigenetic drug application can enhance this inhibition. Frontiers Media S.A. 2022-08-03 /pmc/articles/PMC9382192/ /pubmed/35992806 http://dx.doi.org/10.3389/fonc.2022.873639 Text en Copyright © 2022 Bi, Zhang, Zeng, Liu, Nong, Xie, Li, Lin, Luo, Ge and Xie https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Bi, Shui-Qing Zhang, Qing-Mei Zeng, Xia Liu, Chang Nong, Wei-Xia Xie, Huan Li, Feng Lin, Li-Na Luo, Bin Ge, Ying-Ying Xie, Xiao-Xun Combined treatment with epigenetic agents enhances anti-tumor activity of MAGE-D4 peptide-specific T cells by upregulating the MAGE-D4 expression in glioma |
title | Combined treatment with epigenetic agents enhances anti-tumor activity of MAGE-D4 peptide-specific T cells by upregulating the MAGE-D4 expression in glioma |
title_full | Combined treatment with epigenetic agents enhances anti-tumor activity of MAGE-D4 peptide-specific T cells by upregulating the MAGE-D4 expression in glioma |
title_fullStr | Combined treatment with epigenetic agents enhances anti-tumor activity of MAGE-D4 peptide-specific T cells by upregulating the MAGE-D4 expression in glioma |
title_full_unstemmed | Combined treatment with epigenetic agents enhances anti-tumor activity of MAGE-D4 peptide-specific T cells by upregulating the MAGE-D4 expression in glioma |
title_short | Combined treatment with epigenetic agents enhances anti-tumor activity of MAGE-D4 peptide-specific T cells by upregulating the MAGE-D4 expression in glioma |
title_sort | combined treatment with epigenetic agents enhances anti-tumor activity of mage-d4 peptide-specific t cells by upregulating the mage-d4 expression in glioma |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9382192/ https://www.ncbi.nlm.nih.gov/pubmed/35992806 http://dx.doi.org/10.3389/fonc.2022.873639 |
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