Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering
Multiple myeloma (MM) remains an incurable hematological neoplasm. Neoantigen-specific T cell receptor (TCR)-engineered T (TCR-T) cell therapy is a potential alternative treatment. Particularly, TCRs derived from a third-party donor may cover broad ranges of neoantigens, whereas TCRs in patients suf...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123000761 |
| _version_ | 1797807155474071552 |
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| author | Masahiro Okada Kanako Shimizu Hiroshi Nakazato Satoru Yamasaki Shin-ichiro Fujii |
| author_facet | Masahiro Okada Kanako Shimizu Hiroshi Nakazato Satoru Yamasaki Shin-ichiro Fujii |
| author_sort | Masahiro Okada |
| collection | DOAJ |
| description | Multiple myeloma (MM) remains an incurable hematological neoplasm. Neoantigen-specific T cell receptor (TCR)-engineered T (TCR-T) cell therapy is a potential alternative treatment. Particularly, TCRs derived from a third-party donor may cover broad ranges of neoantigens, whereas TCRs in patients suffering from immune disorders are limited. However, the efficacy and feasibility of treating MM have not been evaluated thoroughly. In this study, we established a system for identifying immunogenic mutant antigens on MM cells and their corresponding TCRs using healthy donor-derived peripheral blood mononuclear cells (PBMCs). Initially, the immune responses to 35 candidate peptides predicted by the immunogenomic analysis were investigated. Peptide-reactive T lymphocytes were enriched, and subsequently, TCR repertoires were determined by single-cell TCR sequencing. Eleven reconstituted TCRs showed mutation-specific responses against 4 peptides. Particularly, we verified the HLA-A∗24:02-binding QYSPVQATF peptide derived from COASY S55Y as the naturally processed epitope across MM cells, making it a promising immune target. Corresponding TCRs specifically recognized COASY S55Y+HLA-A∗24:02+ MM cells and augmented tumoricidal activity. Finally, adoptive cell transfer of TCR-T cells showed objective responses in the xenograft model. We initiatively proposed the utility of tumor mutated antigen-specific TCR genes to suppress MM. Our unique strategy will facilitate further identification of neoantigen-specific TCRs. |
| first_indexed | 2024-03-13T06:18:19Z |
| format | Article |
| id | doaj.art-1927e634d061456e9d0792d7c29cabd2 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-13T06:18:19Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-1927e634d061456e9d0792d7c29cabd22023-06-10T04:27:52ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-06-0129541555Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineeringMasahiro Okada0Kanako Shimizu1Hiroshi Nakazato2Satoru Yamasaki3Shin-ichiro Fujii4Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, JapanLaboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, JapanLaboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, JapanLaboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, JapanLaboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; RIKEN Program for Drug Discovery and Medical Technology Platforms, RIKEN, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Corresponding author Shin-ichiro Fujii, MD, PhD, Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.Multiple myeloma (MM) remains an incurable hematological neoplasm. Neoantigen-specific T cell receptor (TCR)-engineered T (TCR-T) cell therapy is a potential alternative treatment. Particularly, TCRs derived from a third-party donor may cover broad ranges of neoantigens, whereas TCRs in patients suffering from immune disorders are limited. However, the efficacy and feasibility of treating MM have not been evaluated thoroughly. In this study, we established a system for identifying immunogenic mutant antigens on MM cells and their corresponding TCRs using healthy donor-derived peripheral blood mononuclear cells (PBMCs). Initially, the immune responses to 35 candidate peptides predicted by the immunogenomic analysis were investigated. Peptide-reactive T lymphocytes were enriched, and subsequently, TCR repertoires were determined by single-cell TCR sequencing. Eleven reconstituted TCRs showed mutation-specific responses against 4 peptides. Particularly, we verified the HLA-A∗24:02-binding QYSPVQATF peptide derived from COASY S55Y as the naturally processed epitope across MM cells, making it a promising immune target. Corresponding TCRs specifically recognized COASY S55Y+HLA-A∗24:02+ MM cells and augmented tumoricidal activity. Finally, adoptive cell transfer of TCR-T cells showed objective responses in the xenograft model. We initiatively proposed the utility of tumor mutated antigen-specific TCR genes to suppress MM. Our unique strategy will facilitate further identification of neoantigen-specific TCRs.http://www.sciencedirect.com/science/article/pii/S2329050123000761neoantigensmultiple myelomaTCR-T cellsingle-cell TCR sequenceTCR cloningadoptive cell transfer |
| spellingShingle | Masahiro Okada Kanako Shimizu Hiroshi Nakazato Satoru Yamasaki Shin-ichiro Fujii Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering Molecular Therapy: Methods & Clinical Development neoantigens multiple myeloma TCR-T cell single-cell TCR sequence TCR cloning adoptive cell transfer |
| title | Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering |
| title_full | Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering |
| title_fullStr | Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering |
| title_full_unstemmed | Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering |
| title_short | Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering |
| title_sort | detection of mutant antigen specific t cell receptors against multiple myeloma for t cell engineering |
| topic | neoantigens multiple myeloma TCR-T cell single-cell TCR sequence TCR cloning adoptive cell transfer |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123000761 |
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