Residue substitution enhances the immunogenicity of neoepitopes from gastric cancers

Objective: Neoantigens arising from gene mutations in tumors can induce specific immune responses, and neoantigen-based immunotherapies have been tested in clinical trials. Here, we characterized the efficacy of altered neoepitopes in improving immunogenicity against gastric cancer. Methods: Raw dat...

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Autores principales:	Huahui Yu, Jieyu Li, Yuan Yuan, Yu Chen, Jingwen Hong, Chunmei Ye, Wansong Lin, Huijing Chen, Zengqing Guo, Bo Li, Yunbin Ye
Formato:	article
Lenguaje:	EN
Publicado:	China Anti-Cancer Association 2021
Materias:	gastric cancer bioinformatics neoepitope residue substitution immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/12347c1122474a80bf017005f30ba371
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spelling	oai:doaj.org-article:12347c1122474a80bf017005f30ba3712021-11-30T11:27:44ZResidue substitution enhances the immunogenicity of neoepitopes from gastric cancers2095-394110.20892/j.issn.2095-3941.2021.0022https://doaj.org/article/12347c1122474a80bf017005f30ba3712021-11-01T00:00:00Zhttp://www.cancerbiomed.org/index.php/cocr/article/view/1891https://doaj.org/toc/2095-3941Objective: Neoantigens arising from gene mutations in tumors can induce specific immune responses, and neoantigen-based immunotherapies have been tested in clinical trials. Here, we characterized the efficacy of altered neoepitopes in improving immunogenicity against gastric cancer. Methods: Raw data of whole-exome sequencing derived from a patient with gastric cancer were analyzed using bioinformatics methods to identify neoepitopes. Neoepitopes were modified by P1Y (the first amino acid was replaced by tyrosine) and P2L (the second amino acid was replaced by leucine). T2 binding and stability assays were used to detect the affinities between the neoepitopes and the HLA molecules, as well as the stabilities of complexes. Dendritic cells (DCs) presented with neoepitopes stimulated naïve CD8+ T cells to induce specific cytotoxic T lymphocytes. ELISA and carboxyfluorescein succinimidyl ester were used to detect IFN-γ and TNF-α levels, and T cell proliferation. Perforin was detected by flow cytometry. The cytotoxicity of T cells was determined using the lactate dehydrogenase assay. Results: Bioinformatics analysis, T2 binding, and stability assays indicated that residue substitution increased the affinity between neoepitopes and HLA molecules, as well as the stabilities of complexes. DCs presented with altered neoepitopes stimulated CD8+T cells to release more IFN-γ and had a greater effect on promoting proliferation than wild-type neoepitopes. CD8+T cells stimulated with altered neoepitopes killed more wild-type neoepitope-pulsed T2 cells than those stimulated with wild-type neoepitopes, by secreting more IFN-γ, TNF-α, and perforin. Conclusions: Altered neoepitopes exhibited greater immunogenicity than wild-type neoepitopes. Residue substitution could be used as a new strategy for immunotherapy to target neoantigens.Huahui YuJieyu LiYuan YuanYu ChenJingwen HongChunmei YeWansong LinHuijing ChenZengqing GuoBo LiYunbin YeChina Anti-Cancer Associationarticlegastric cancerbioinformaticsneoepitoperesidue substitutionimmunotherapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancer Biology & Medicine, Vol 18, Iss 4, Pp 1053-1065 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	gastric cancer bioinformatics neoepitope residue substitution immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	gastric cancer bioinformatics neoepitope residue substitution immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Huahui Yu Jieyu Li Yuan Yuan Yu Chen Jingwen Hong Chunmei Ye Wansong Lin Huijing Chen Zengqing Guo Bo Li Yunbin Ye Residue substitution enhances the immunogenicity of neoepitopes from gastric cancers
description	Objective: Neoantigens arising from gene mutations in tumors can induce specific immune responses, and neoantigen-based immunotherapies have been tested in clinical trials. Here, we characterized the efficacy of altered neoepitopes in improving immunogenicity against gastric cancer. Methods: Raw data of whole-exome sequencing derived from a patient with gastric cancer were analyzed using bioinformatics methods to identify neoepitopes. Neoepitopes were modified by P1Y (the first amino acid was replaced by tyrosine) and P2L (the second amino acid was replaced by leucine). T2 binding and stability assays were used to detect the affinities between the neoepitopes and the HLA molecules, as well as the stabilities of complexes. Dendritic cells (DCs) presented with neoepitopes stimulated naïve CD8+ T cells to induce specific cytotoxic T lymphocytes. ELISA and carboxyfluorescein succinimidyl ester were used to detect IFN-γ and TNF-α levels, and T cell proliferation. Perforin was detected by flow cytometry. The cytotoxicity of T cells was determined using the lactate dehydrogenase assay. Results: Bioinformatics analysis, T2 binding, and stability assays indicated that residue substitution increased the affinity between neoepitopes and HLA molecules, as well as the stabilities of complexes. DCs presented with altered neoepitopes stimulated CD8+T cells to release more IFN-γ and had a greater effect on promoting proliferation than wild-type neoepitopes. CD8+T cells stimulated with altered neoepitopes killed more wild-type neoepitope-pulsed T2 cells than those stimulated with wild-type neoepitopes, by secreting more IFN-γ, TNF-α, and perforin. Conclusions: Altered neoepitopes exhibited greater immunogenicity than wild-type neoepitopes. Residue substitution could be used as a new strategy for immunotherapy to target neoantigens.
format	article
author	Huahui Yu Jieyu Li Yuan Yuan Yu Chen Jingwen Hong Chunmei Ye Wansong Lin Huijing Chen Zengqing Guo Bo Li Yunbin Ye
author_facet	Huahui Yu Jieyu Li Yuan Yuan Yu Chen Jingwen Hong Chunmei Ye Wansong Lin Huijing Chen Zengqing Guo Bo Li Yunbin Ye
author_sort	Huahui Yu
title	Residue substitution enhances the immunogenicity of neoepitopes from gastric cancers
title_short	Residue substitution enhances the immunogenicity of neoepitopes from gastric cancers
title_full	Residue substitution enhances the immunogenicity of neoepitopes from gastric cancers
title_fullStr	Residue substitution enhances the immunogenicity of neoepitopes from gastric cancers
title_full_unstemmed	Residue substitution enhances the immunogenicity of neoepitopes from gastric cancers
title_sort	residue substitution enhances the immunogenicity of neoepitopes from gastric cancers
publisher	China Anti-Cancer Association
publishDate	2021
url	https://doaj.org/article/12347c1122474a80bf017005f30ba371
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Residue substitution enhances the immunogenicity of neoepitopes from gastric cancers

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