Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer
Endocrine therapy has shown significant clinical efficacy in estrogen receptor alpha (ERα)-positive breast cancer management, but the emergence of therapy-resistant mutations significantly undermines treatment outcomes, frequently leading to disease progression and metastasis. Among these resistance...
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| Format: | Article |
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Elsevier
2025-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000806 |
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| author | Mingshuang Wang Liwei Pang Yingjie Sun Jingjing Han Jiani Fan Wenhui Shen Xiaonan Hu Bingqian Yang Haoming Ning Yanan Kong Duo Li Wenshan Zhao Ranran Shi Ling Ran Yuanming Qi Yahong Wu |
| author_facet | Mingshuang Wang Liwei Pang Yingjie Sun Jingjing Han Jiani Fan Wenhui Shen Xiaonan Hu Bingqian Yang Haoming Ning Yanan Kong Duo Li Wenshan Zhao Ranran Shi Ling Ran Yuanming Qi Yahong Wu |
| author_sort | Mingshuang Wang |
| collection | DOAJ |
| description | Endocrine therapy has shown significant clinical efficacy in estrogen receptor alpha (ERα)-positive breast cancer management, but the emergence of therapy-resistant mutations significantly undermines treatment outcomes, frequently leading to disease progression and metastasis. Among these resistance mechanisms, mutations in the ESR1 gene are particularly prevalent, detectable in 76% of endocrine therapy-resistant tumor specimens. The identification of immunogenic neoepitopes derived from mutant ESR1 offers a promising therapeutic avenue for patients with endocrine therapy-resistant breast cancer. In this study, we systematically investigated the mutational landscape of ESR1 across various cancer types, with particular emphasis on mutation frequency and spectrum analysis. Our findings revealed that non-synonymous ESR1 mutations predominantly occurred in breast cancer, clustering at four distinct hotspot sites: K303, E380, Y537 and D538. We further characterized the mutation prevalence at these hotspots across different breast cancer subtypes. Through comprehensive screening, we identified eight human leukocyte antigen (HLA)-A*0201 restricted immunogenic neoepitopes derived from ESR1 hotspot mutations. These neoepitopes demonstrated the capacity to elicit specific cytotoxic T lymphocytes (CTLs) responses both in vitro and in vivo. The induced CTLs exhibited specific recognition and cytotoxic activity against both T2A2 cells loaded with mutant neoepitopes and HLA-A*0201-positive breast cancer cells transfected with minigene encoding mutant neoepitopes. Notably, adoptive transfer of T cells primed with a peptide pool containing these eight neoepitopes significantly suppressed tumor growth and enhanced CD8+ T cells infiltration within tumor tissue. These findings suggest that the identified neoepitopes represent promising candidates for the development of tumor shared neoantigen vaccines. |
| format | Article |
| id | doaj-art-b19fb7fd4cdf4e648230ba5fd6fa0e3a |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-b19fb7fd4cdf4e648230ba5fd6fa0e3a2025-08-20T03:58:41ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-09-016710120010.1016/j.neo.2025.101200Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancerMingshuang Wang0Liwei Pang1Yingjie Sun2Jingjing Han3Jiani Fan4Wenhui Shen5Xiaonan Hu6Bingqian Yang7Haoming Ning8Yanan Kong9Duo Li10Wenshan Zhao11Ranran Shi12Ling Ran13Yuanming Qi14Yahong Wu15School of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou 450001, China; International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou 450001, ChinaDepartment of Basic Medical Sciences, Luohe Medical College, Luohe 462000, ChinaDepartment of Basic Medical Sciences, Luohe Medical College, Luohe 462000, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou 450001, China; International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou 450001, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou 450001, China; International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou 450001, China; Corresponding author.Endocrine therapy has shown significant clinical efficacy in estrogen receptor alpha (ERα)-positive breast cancer management, but the emergence of therapy-resistant mutations significantly undermines treatment outcomes, frequently leading to disease progression and metastasis. Among these resistance mechanisms, mutations in the ESR1 gene are particularly prevalent, detectable in 76% of endocrine therapy-resistant tumor specimens. The identification of immunogenic neoepitopes derived from mutant ESR1 offers a promising therapeutic avenue for patients with endocrine therapy-resistant breast cancer. In this study, we systematically investigated the mutational landscape of ESR1 across various cancer types, with particular emphasis on mutation frequency and spectrum analysis. Our findings revealed that non-synonymous ESR1 mutations predominantly occurred in breast cancer, clustering at four distinct hotspot sites: K303, E380, Y537 and D538. We further characterized the mutation prevalence at these hotspots across different breast cancer subtypes. Through comprehensive screening, we identified eight human leukocyte antigen (HLA)-A*0201 restricted immunogenic neoepitopes derived from ESR1 hotspot mutations. These neoepitopes demonstrated the capacity to elicit specific cytotoxic T lymphocytes (CTLs) responses both in vitro and in vivo. The induced CTLs exhibited specific recognition and cytotoxic activity against both T2A2 cells loaded with mutant neoepitopes and HLA-A*0201-positive breast cancer cells transfected with minigene encoding mutant neoepitopes. Notably, adoptive transfer of T cells primed with a peptide pool containing these eight neoepitopes significantly suppressed tumor growth and enhanced CD8+ T cells infiltration within tumor tissue. These findings suggest that the identified neoepitopes represent promising candidates for the development of tumor shared neoantigen vaccines.http://www.sciencedirect.com/science/article/pii/S1476558625000806ESR1Hotspot mutationsNeoepitopesHLA-A2Immunotherapy |
| spellingShingle | Mingshuang Wang Liwei Pang Yingjie Sun Jingjing Han Jiani Fan Wenhui Shen Xiaonan Hu Bingqian Yang Haoming Ning Yanan Kong Duo Li Wenshan Zhao Ranran Shi Ling Ran Yuanming Qi Yahong Wu Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer Neoplasia: An International Journal for Oncology Research ESR1 Hotspot mutations Neoepitopes HLA-A2 Immunotherapy |
| title | Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer |
| title_full | Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer |
| title_fullStr | Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer |
| title_full_unstemmed | Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer |
| title_short | Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer |
| title_sort | screening and identification of hla a2 restricted neoepitopes for immunotherapy in endocrine therapy resistant breast cancer |
| topic | ESR1 Hotspot mutations Neoepitopes HLA-A2 Immunotherapy |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000806 |
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