A rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells
Abstract Background High-affinity tumor antigen-specific T-cell receptor (TCR) gene is required to engineer potent T cells for therapeutic treatment of cancer patients. However, discovery of suitable therapeutic TCR genes is hampered by the fact that naturally occurring tumor antigen-specific TCRs a...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-018-0467-y |
| _version_ | 1824022459980972032 |
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| author | Junko Matsuzaki Takemasa Tsuji Thinle Chodon Courtney Ryan Richard C. Koya Kunle Odunsi |
| author_facet | Junko Matsuzaki Takemasa Tsuji Thinle Chodon Courtney Ryan Richard C. Koya Kunle Odunsi |
| author_sort | Junko Matsuzaki |
| collection | DOAJ |
| description | Abstract Background High-affinity tumor antigen-specific T-cell receptor (TCR) gene is required to engineer potent T cells for therapeutic treatment of cancer patients. However, discovery of suitable therapeutic TCR genes is hampered by the fact that naturally occurring tumor antigen-specific TCRs are generally of low-affinity, and artificial modification of TCRs can mediate cross-reactivity to other antigens expressed in normal tissues. Here, we discovered a naturally occurring T-cell clone which expressed high-affinity HLA-A*02:01 (A*02)-restricted TCR against NY-ESO-1 from a patient who had NY-ESO-1-expressing ovarian tumor. Methods A*02-restricted NY-ESO-1-specific T-cell clones were established from peripheral blood of patients who had NY-ESO-1-expressing ovarian tumors. TCR α and β chain genes were retrovirally transduced into polyclonally activated T cells. Phenotype and function of the parental and TCR-transduced T cells were analyzed by flow cytometry, ELISA and cytotoxicity assay. In vivo therapeutic efficacy was investigated in a xenograft model using NOD/SCID/IL-2Rγ-deficient (NSG) mice. Results A rare population of NY-ESO-1-specific T cells, which we named 19305DP, expressed cell surface CD4, CD8α, and CD8β but not CD56 and recognized A*02+NY-ESO-1+ cancer cell lines in a CD4- and CD8-independent manner. 19305DP showed a gene expression profile that is consistent with a mixed profile of CD4+ and CD8+ single-positive T cells. Both CD4+ and CD8+ T cells that were retrovirally transduced with 19305DP-derived TCR gene (19305DP-TCR) showed strong reactivity against A*02+NY-ESO-1+ cancer cells, whereas TCR genes from the conventional A*02-restricted NY-ESO-1-specific CD8+ single-positive T-cell clones functioned only in CD8+ T cells. Both 19305DP-TCR gene-engineered CD4+ and CD8+ T cells eliminated A*02+NY-ESO-1+ tumor xenografts in NSG mice. Finally, based on reactivity against a series of alanine-substituted peptides and a panel of normal human tissue-derived primary cells, 19305DP-TCR was predicted to have no cross-reactivity against any human non-NY-ESO-1 proteins. Conclusion Together, our results indicate that the naturally occurring 19305DP-TCR derived from CD4+CD8+ double-positive αβ T cells, is a promising therapeutic TCR gene for effective and safe adoptive T-cell therapy in A*02+ patients with NY-ESO-1-expressing tumor. |
| first_indexed | 2024-12-19T09:21:03Z |
| format | Article |
| id | doaj.art-9e97bbea02b24ef891cc5d1f3e5ced8d |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-19T09:21:03Z |
| publishDate | 2019-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-9e97bbea02b24ef891cc5d1f3e5ced8d2022-12-21T20:27:58ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-01-017111810.1186/s40425-018-0467-yA rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cellsJunko Matsuzaki0Takemasa Tsuji1Thinle Chodon2Courtney Ryan3Richard C. Koya4Kunle Odunsi5Center for Immunotherapy, Department of Immunology, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Department of Immunology, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Department of Immunology, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Department of Immunology, Roswell Park Comprehensive Cancer CenterCenter for Immunotherapy, Department of Immunology, Roswell Park Comprehensive Cancer CenterAbstract Background High-affinity tumor antigen-specific T-cell receptor (TCR) gene is required to engineer potent T cells for therapeutic treatment of cancer patients. However, discovery of suitable therapeutic TCR genes is hampered by the fact that naturally occurring tumor antigen-specific TCRs are generally of low-affinity, and artificial modification of TCRs can mediate cross-reactivity to other antigens expressed in normal tissues. Here, we discovered a naturally occurring T-cell clone which expressed high-affinity HLA-A*02:01 (A*02)-restricted TCR against NY-ESO-1 from a patient who had NY-ESO-1-expressing ovarian tumor. Methods A*02-restricted NY-ESO-1-specific T-cell clones were established from peripheral blood of patients who had NY-ESO-1-expressing ovarian tumors. TCR α and β chain genes were retrovirally transduced into polyclonally activated T cells. Phenotype and function of the parental and TCR-transduced T cells were analyzed by flow cytometry, ELISA and cytotoxicity assay. In vivo therapeutic efficacy was investigated in a xenograft model using NOD/SCID/IL-2Rγ-deficient (NSG) mice. Results A rare population of NY-ESO-1-specific T cells, which we named 19305DP, expressed cell surface CD4, CD8α, and CD8β but not CD56 and recognized A*02+NY-ESO-1+ cancer cell lines in a CD4- and CD8-independent manner. 19305DP showed a gene expression profile that is consistent with a mixed profile of CD4+ and CD8+ single-positive T cells. Both CD4+ and CD8+ T cells that were retrovirally transduced with 19305DP-derived TCR gene (19305DP-TCR) showed strong reactivity against A*02+NY-ESO-1+ cancer cells, whereas TCR genes from the conventional A*02-restricted NY-ESO-1-specific CD8+ single-positive T-cell clones functioned only in CD8+ T cells. Both 19305DP-TCR gene-engineered CD4+ and CD8+ T cells eliminated A*02+NY-ESO-1+ tumor xenografts in NSG mice. Finally, based on reactivity against a series of alanine-substituted peptides and a panel of normal human tissue-derived primary cells, 19305DP-TCR was predicted to have no cross-reactivity against any human non-NY-ESO-1 proteins. Conclusion Together, our results indicate that the naturally occurring 19305DP-TCR derived from CD4+CD8+ double-positive αβ T cells, is a promising therapeutic TCR gene for effective and safe adoptive T-cell therapy in A*02+ patients with NY-ESO-1-expressing tumor.http://link.springer.com/article/10.1186/s40425-018-0467-yNY-ESO-1TCR gene-engineeringCD4+CD8+ double-positive T cellsHLA-A*02:01Anti-tumor functionAdoptive cell therapy |
| spellingShingle | Junko Matsuzaki Takemasa Tsuji Thinle Chodon Courtney Ryan Richard C. Koya Kunle Odunsi A rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells Journal for ImmunoTherapy of Cancer NY-ESO-1 TCR gene-engineering CD4+CD8+ double-positive T cells HLA-A*02:01 Anti-tumor function Adoptive cell therapy |
| title | A rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells |
| title_full | A rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells |
| title_fullStr | A rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells |
| title_full_unstemmed | A rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells |
| title_short | A rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells |
| title_sort | rare population of tumor antigen specific cd4 cd8 double positive αβ t lymphocytes uniquely provide cd8 independent tcr genes for engineering therapeutic t cells |
| topic | NY-ESO-1 TCR gene-engineering CD4+CD8+ double-positive T cells HLA-A*02:01 Anti-tumor function Adoptive cell therapy |
| url | http://link.springer.com/article/10.1186/s40425-018-0467-y |
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