Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy
Background Adoptive transfer of patient’s T cells, engineered to express a T cell receptor (TCR) with defined novel antigen specificity, is a convenient form of cancer therapy. In most cases, major histocompatibility complex (MHC) I-restricted TCRs are expressed in CD8+ T cells and the development o...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/2/e006001.full |
| _version_ | 1797894814065229824 |
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| author | Thomas Blankenstein Natalia Plewa Lucia Poncette |
| author_facet | Thomas Blankenstein Natalia Plewa Lucia Poncette |
| author_sort | Thomas Blankenstein |
| collection | DOAJ |
| description | Background Adoptive transfer of patient’s T cells, engineered to express a T cell receptor (TCR) with defined novel antigen specificity, is a convenient form of cancer therapy. In most cases, major histocompatibility complex (MHC) I-restricted TCRs are expressed in CD8+ T cells and the development of CD4+ T cells engineered to express an MHC II-restricted TCR lacks behind. Critical is the choice of the target antigen, whether the epitope is efficiently processed and binds with high affinity to MHC molecules. A mutation in the transforming growth factor β receptor 2 (TGFβR2(-1)) gene creates a frameshift peptide caused by the deletion of one adenine (-1) within a microsatellite sequence. This somatic mutation is recurrent in microsatellite instable colorectal and gastric cancers and, therefore, is a truly tumor-specific antigen detected in many patients.Methods ABabDR4 mice, which express a diverse human TCR repertoire restricted to human MHC II molecule HLA-DRA/DRB1*0401 (HLA-DR4), were immunized with the TGFβR2(-1) peptide and TGFβR2(-1)-specific TCRs were isolated from responding CD4+ T cells. The TGFβR2(-1)-specific TCRs were expressed in human CD4+ T cells and their potency and safety profile were assessed by co-cultures and other functional assays.Results We demonstrated that TGFβR2(-1) neoantigen is immunogenic and elicited CD4+ T cell responses in ABabDR4 mice. When expressed in human CD4+ T cells, the HLA-DR4 restricted TGFβR2(-1)-specific TCRs induced IFNy expression at low TGFβR2(-1) peptide amounts. The TGFβR2(-1)-specific TCRs recognized HLA-DR4+ lymphoblastoid cells, which endogenously processed and presented the neoantigen, and colorectal cancer cell lines SW48 and HCT116 naturally expressing the TGFβR2(-1) mutation. No MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif were observed, indicating the safety of the TCRs.Conclusions The data suggest that HLA-DR4-restricted TCRs specific for the TGFβR2(-1) recurrent neoantigen can be valuable candidates for adoptive T cell therapy of a sizeable number of patients with cancer. |
| first_indexed | 2024-04-10T07:16:27Z |
| format | Article |
| id | doaj.art-9ee2fb67fa174601b37ca3681f3fb742 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-10T07:16:27Z |
| publishDate | 2023-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-9ee2fb67fa174601b37ca3681f3fb7422023-02-25T09:30:13ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-02-0111210.1136/jitc-2022-006001Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapyThomas Blankenstein0Natalia Plewa1Lucia Poncette2Max Delbruck Centre for Molecular Medicine, Berlin, GermanyMax Delbruck Centre for Molecular Medicine, Berlin, GermanyMax Delbruck Centre for Molecular Medicine, Berlin, GermanyBackground Adoptive transfer of patient’s T cells, engineered to express a T cell receptor (TCR) with defined novel antigen specificity, is a convenient form of cancer therapy. In most cases, major histocompatibility complex (MHC) I-restricted TCRs are expressed in CD8+ T cells and the development of CD4+ T cells engineered to express an MHC II-restricted TCR lacks behind. Critical is the choice of the target antigen, whether the epitope is efficiently processed and binds with high affinity to MHC molecules. A mutation in the transforming growth factor β receptor 2 (TGFβR2(-1)) gene creates a frameshift peptide caused by the deletion of one adenine (-1) within a microsatellite sequence. This somatic mutation is recurrent in microsatellite instable colorectal and gastric cancers and, therefore, is a truly tumor-specific antigen detected in many patients.Methods ABabDR4 mice, which express a diverse human TCR repertoire restricted to human MHC II molecule HLA-DRA/DRB1*0401 (HLA-DR4), were immunized with the TGFβR2(-1) peptide and TGFβR2(-1)-specific TCRs were isolated from responding CD4+ T cells. The TGFβR2(-1)-specific TCRs were expressed in human CD4+ T cells and their potency and safety profile were assessed by co-cultures and other functional assays.Results We demonstrated that TGFβR2(-1) neoantigen is immunogenic and elicited CD4+ T cell responses in ABabDR4 mice. When expressed in human CD4+ T cells, the HLA-DR4 restricted TGFβR2(-1)-specific TCRs induced IFNy expression at low TGFβR2(-1) peptide amounts. The TGFβR2(-1)-specific TCRs recognized HLA-DR4+ lymphoblastoid cells, which endogenously processed and presented the neoantigen, and colorectal cancer cell lines SW48 and HCT116 naturally expressing the TGFβR2(-1) mutation. No MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif were observed, indicating the safety of the TCRs.Conclusions The data suggest that HLA-DR4-restricted TCRs specific for the TGFβR2(-1) recurrent neoantigen can be valuable candidates for adoptive T cell therapy of a sizeable number of patients with cancer.https://jitc.bmj.com/content/11/2/e006001.full |
| spellingShingle | Thomas Blankenstein Natalia Plewa Lucia Poncette Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy Journal for ImmunoTherapy of Cancer |
| title | Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy |
| title_full | Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy |
| title_fullStr | Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy |
| title_full_unstemmed | Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy |
| title_short | Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy |
| title_sort | generation of tgfβr2 1 neoantigen specific hla dr4 restricted t cell receptors for cancer therapy |
| url | https://jitc.bmj.com/content/11/2/e006001.full |
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