Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer
Abstract Background Efficient identification of neoantigen-specific T-cell responses in epithelial ovarian cancer (EOC) remains a challenge. Existing investigations of spontaneous T-cell response to tumor neoepitope in EOC have taken the approach of comprehensive screening all neoantigen candidates,...
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BMJ Publishing Group
2019-06-01
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Series: | Journal for ImmunoTherapy of Cancer |
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Online Access: | http://link.springer.com/article/10.1186/s40425-019-0629-6 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Song Liu Junko Matsuzaki Lei Wei Takemasa Tsuji Sebastiano Battaglia Qiang Hu Eduardo Cortes Laiping Wong Li Yan Mark Long Anthony Miliotto Nicholas W. Bateman Shashikant B. Lele Thinle Chodon Richard C. Koya Song Yao Qianqian Zhu Thomas P. Conrads Jianmin Wang George L. Maxwell Amit A. Lugade Kunle Odunsi |
spellingShingle |
Song Liu Junko Matsuzaki Lei Wei Takemasa Tsuji Sebastiano Battaglia Qiang Hu Eduardo Cortes Laiping Wong Li Yan Mark Long Anthony Miliotto Nicholas W. Bateman Shashikant B. Lele Thinle Chodon Richard C. Koya Song Yao Qianqian Zhu Thomas P. Conrads Jianmin Wang George L. Maxwell Amit A. Lugade Kunle Odunsi Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer Journal for ImmunoTherapy of Cancer Neoantigen Ovarian cancer CD4+ T-cells CD8+ T-cells Anti-tumor effect T-cell receptor |
author_facet |
Song Liu Junko Matsuzaki Lei Wei Takemasa Tsuji Sebastiano Battaglia Qiang Hu Eduardo Cortes Laiping Wong Li Yan Mark Long Anthony Miliotto Nicholas W. Bateman Shashikant B. Lele Thinle Chodon Richard C. Koya Song Yao Qianqian Zhu Thomas P. Conrads Jianmin Wang George L. Maxwell Amit A. Lugade Kunle Odunsi |
author_sort |
Song Liu |
title |
Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer |
title_short |
Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer |
title_full |
Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer |
title_fullStr |
Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer |
title_full_unstemmed |
Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer |
title_sort |
efficient identification of neoantigen-specific t-cell responses in advanced human ovarian cancer |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2019-06-01 |
description |
Abstract Background Efficient identification of neoantigen-specific T-cell responses in epithelial ovarian cancer (EOC) remains a challenge. Existing investigations of spontaneous T-cell response to tumor neoepitope in EOC have taken the approach of comprehensive screening all neoantigen candidates, with a validation rate of 0.5–2%. Methods Whole-exome and transcriptome sequencing analysis of treatment-naive EOC patients were performed to identify neoantigen candidates, and the immunogenicity of prioritized neoantigens was evaluated by analyzing spontaneous neoantigen-specfic CD4+ and CD8+ T-cell responses in the tumor and/or peripheral blood. The biological relevance of neoantigen-specific T-cell lines and clones were analyzed by evaluating the capacity of autologous ovarian tumor recognition. Genetic transfer of T-cell receptor (TCR) from these neoantigen-specific T-cell clones into peripheral blood T-cells was conducted to generate neoepitope-specific T-cells. The molecular signature associated with positive neoantigen T-cell responses was investigated, and the impacts of expression level and lymphocyte source on neoantigen identification were explored. Results Using a small subset of prioritized neoantigen candidates, we were able to detect spontaneous CD4+ and/or CD8+ T-cell responses against neoepitopes from autologous lymphocytes in half of treatment-naïve EOC patients, with a significantly improved validation rate of 19%. Tumors from patients exhibiting neoantigen-specific T-cell responses exhibited a signature of upregulated antigen processing and presentation machinery, which was also associated with favorable patient survival in the TCGA ovarian cohort. T-cells specific against two mutated cancer-associated genes, NUP214 and JAK1, recognized autologous tumors. Gene-engineering with TCR from these neoantigen-specific T-cell clones conferred neoantigen-reactivity to peripheral T-cells. Conclusions Our study demonstrated the feasibility of efficiently identifying both CD4+ and CD8+ neoantigen-specific T-cells in EOC. Autologous lymphocytes genetically engineered with tumor antigen-specific TCR can be used to generate cells for use in the personalized adoptive T-cell transfer immunotherapy. |
topic |
Neoantigen Ovarian cancer CD4+ T-cells CD8+ T-cells Anti-tumor effect T-cell receptor |
url |
http://link.springer.com/article/10.1186/s40425-019-0629-6 |
work_keys_str_mv |
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doaj-7412361f6c6849f692fd6d0c0b30a2d42020-11-25T01:41:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-06-017111710.1186/s40425-019-0629-6Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancerSong Liu0Junko Matsuzaki1Lei Wei2Takemasa Tsuji3Sebastiano Battaglia4Qiang Hu5Eduardo Cortes6Laiping Wong7Li Yan8Mark Long9Anthony Miliotto10Nicholas W. Bateman11Shashikant B. Lele12Thinle Chodon13Richard C. Koya14Song Yao15Qianqian Zhu16Thomas P. Conrads17Jianmin Wang18George L. Maxwell19Amit A. Lugade20Kunle Odunsi21Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterGynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical CenterDepartment of Gynecologic Oncology, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterDepartment of Cancer Prevention and Control, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterGynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterGynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterAbstract Background Efficient identification of neoantigen-specific T-cell responses in epithelial ovarian cancer (EOC) remains a challenge. Existing investigations of spontaneous T-cell response to tumor neoepitope in EOC have taken the approach of comprehensive screening all neoantigen candidates, with a validation rate of 0.5–2%. Methods Whole-exome and transcriptome sequencing analysis of treatment-naive EOC patients were performed to identify neoantigen candidates, and the immunogenicity of prioritized neoantigens was evaluated by analyzing spontaneous neoantigen-specfic CD4+ and CD8+ T-cell responses in the tumor and/or peripheral blood. The biological relevance of neoantigen-specific T-cell lines and clones were analyzed by evaluating the capacity of autologous ovarian tumor recognition. Genetic transfer of T-cell receptor (TCR) from these neoantigen-specific T-cell clones into peripheral blood T-cells was conducted to generate neoepitope-specific T-cells. The molecular signature associated with positive neoantigen T-cell responses was investigated, and the impacts of expression level and lymphocyte source on neoantigen identification were explored. Results Using a small subset of prioritized neoantigen candidates, we were able to detect spontaneous CD4+ and/or CD8+ T-cell responses against neoepitopes from autologous lymphocytes in half of treatment-naïve EOC patients, with a significantly improved validation rate of 19%. Tumors from patients exhibiting neoantigen-specific T-cell responses exhibited a signature of upregulated antigen processing and presentation machinery, which was also associated with favorable patient survival in the TCGA ovarian cohort. T-cells specific against two mutated cancer-associated genes, NUP214 and JAK1, recognized autologous tumors. Gene-engineering with TCR from these neoantigen-specific T-cell clones conferred neoantigen-reactivity to peripheral T-cells. Conclusions Our study demonstrated the feasibility of efficiently identifying both CD4+ and CD8+ neoantigen-specific T-cells in EOC. Autologous lymphocytes genetically engineered with tumor antigen-specific TCR can be used to generate cells for use in the personalized adoptive T-cell transfer immunotherapy.http://link.springer.com/article/10.1186/s40425-019-0629-6NeoantigenOvarian cancerCD4+ T-cellsCD8+ T-cellsAnti-tumor effectT-cell receptor |