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Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells

The identification of novel biomarkers and therapeutic targets in advanced cancer is critical for improving cancer diagnosis and therapeutics. Survivin (SV) is highly expressed predominantly in most cancer cells and tissues but is absent or undetectable in terminally differentiated normal adult tiss...

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Autores principales: Chen, Qiuqiang, Jia, Gang, Zhao, Xiaolei, Bao, Ying, Zhang, Yu, Ozkan, Cengiz, Minev, Boris, Ma, Wenxue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496070/
https://www.ncbi.nlm.nih.gov/pubmed/33102521
http://dx.doi.org/10.3389/fmolb.2020.570003
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author Chen, Qiuqiang
Jia, Gang
Zhao, Xiaolei
Bao, Ying
Zhang, Yu
Ozkan, Cengiz
Minev, Boris
Ma, Wenxue
author_facet Chen, Qiuqiang
Jia, Gang
Zhao, Xiaolei
Bao, Ying
Zhang, Yu
Ozkan, Cengiz
Minev, Boris
Ma, Wenxue
author_sort Chen, Qiuqiang
collection PubMed
description The identification of novel biomarkers and therapeutic targets in advanced cancer is critical for improving cancer diagnosis and therapeutics. Survivin (SV) is highly expressed predominantly in most cancer cells and tissues but is absent or undetectable in terminally differentiated normal adult tissues. Therefore, it functions as an almost universal tumor antigen. Peptides are short chains of amino acids linked by peptide bonds. To obtain novel SV decamers that are able to induce SV-specific cytotoxic T lymphocytes (CTLs) with a higher cytotoxic efficiency against cancer cells, major histocompatibility complex (MHC) peptide binding algorithms were conducted to predict nine modified SV(95) decamers (from SV(95–2) to SV(95–10)) based on the natural SV(95–104) peptide sequence of ELTLGEFLKL (here defined as SV(95–1)). The fluorescent density of each SV(95) peptide was determined by a MHC stability assay, followed by the generation of SV(95)-specific CTLs with each SV(95) peptide (from SV(95–1) to SV(95–10)) and human dendritic cells (DCs) loaded with Poly(lactic-co-glycolic) acid (PLGA) nanoparticles encapsulated with SV(95) peptide. Finally, IFN-γ ELISpot and CytoTox 96(®) Non-Radioactive Cytotoxicity Assays were employed to verify their cytotoxic efficiency of the SV(95)-specific CTLs generated with the corresponding artificial antigen presenting cells (aAPCs) containing SV(95) (SV(95–1) to SV(95–10)) peptide. Furthermore, the cytotoxicity of the SV(95) specific CTLs generated with nine mutated SV(95) peptides was compared to the one generated with natural SV(95–1) peptide and TIL2080 cells. The results indicated that the HLA-A2-restricted mutated SV(95) epitope decamers (SV(95–6) and SV(95–7)) showed significant higher binding ability compared to natural peptide SV(95–1) in MHC stability assay. More importantly, SV(95–)specific CTLs with higher cytotoxicity were successfully induced with both SV(95–6) and SV(95–7) peptides, which significantly eliminated target cells (not only SV(95–1) peptide pulsed T2 cells, but also both HLA-A2 and SV positive cancer cells) when compared to those generated with natural SV(95–1) peptide and TIL2080 cells. These findings suggest that the SV(95–6) and SV(95–7) peptides are two novel HLA-A2-restricted CTL epitopes and may be useful for the immunotherapy for patients with survivin expressing cancer.
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spelling pubmed-74960702020-10-22 Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells Chen, Qiuqiang Jia, Gang Zhao, Xiaolei Bao, Ying Zhang, Yu Ozkan, Cengiz Minev, Boris Ma, Wenxue Front Mol Biosci Molecular Biosciences The identification of novel biomarkers and therapeutic targets in advanced cancer is critical for improving cancer diagnosis and therapeutics. Survivin (SV) is highly expressed predominantly in most cancer cells and tissues but is absent or undetectable in terminally differentiated normal adult tissues. Therefore, it functions as an almost universal tumor antigen. Peptides are short chains of amino acids linked by peptide bonds. To obtain novel SV decamers that are able to induce SV-specific cytotoxic T lymphocytes (CTLs) with a higher cytotoxic efficiency against cancer cells, major histocompatibility complex (MHC) peptide binding algorithms were conducted to predict nine modified SV(95) decamers (from SV(95–2) to SV(95–10)) based on the natural SV(95–104) peptide sequence of ELTLGEFLKL (here defined as SV(95–1)). The fluorescent density of each SV(95) peptide was determined by a MHC stability assay, followed by the generation of SV(95)-specific CTLs with each SV(95) peptide (from SV(95–1) to SV(95–10)) and human dendritic cells (DCs) loaded with Poly(lactic-co-glycolic) acid (PLGA) nanoparticles encapsulated with SV(95) peptide. Finally, IFN-γ ELISpot and CytoTox 96(®) Non-Radioactive Cytotoxicity Assays were employed to verify their cytotoxic efficiency of the SV(95)-specific CTLs generated with the corresponding artificial antigen presenting cells (aAPCs) containing SV(95) (SV(95–1) to SV(95–10)) peptide. Furthermore, the cytotoxicity of the SV(95) specific CTLs generated with nine mutated SV(95) peptides was compared to the one generated with natural SV(95–1) peptide and TIL2080 cells. The results indicated that the HLA-A2-restricted mutated SV(95) epitope decamers (SV(95–6) and SV(95–7)) showed significant higher binding ability compared to natural peptide SV(95–1) in MHC stability assay. More importantly, SV(95–)specific CTLs with higher cytotoxicity were successfully induced with both SV(95–6) and SV(95–7) peptides, which significantly eliminated target cells (not only SV(95–1) peptide pulsed T2 cells, but also both HLA-A2 and SV positive cancer cells) when compared to those generated with natural SV(95–1) peptide and TIL2080 cells. These findings suggest that the SV(95–6) and SV(95–7) peptides are two novel HLA-A2-restricted CTL epitopes and may be useful for the immunotherapy for patients with survivin expressing cancer. Frontiers Media S.A. 2020-09-02 /pmc/articles/PMC7496070/ /pubmed/33102521 http://dx.doi.org/10.3389/fmolb.2020.570003 Text en Copyright © 2020 Chen, Jia, Zhao, Bao, Zhang, Ozkan, Minev and Ma. http://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 Molecular Biosciences
Chen, Qiuqiang
Jia, Gang
Zhao, Xiaolei
Bao, Ying
Zhang, Yu
Ozkan, Cengiz
Minev, Boris
Ma, Wenxue
Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells
title Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells
title_full Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells
title_fullStr Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells
title_full_unstemmed Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells
title_short Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells
title_sort novel survivin peptides screened with computer algorithm induce cytotoxic t lymphocytes with higher cytotoxic efficiency to cancer cells
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496070/
https://www.ncbi.nlm.nih.gov/pubmed/33102521
http://dx.doi.org/10.3389/fmolb.2020.570003
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