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Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy

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Item Type:Article
Title:Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy
Creators Name:Plewa, N. and Poncette, L. and Blankenstein, T.
Abstract: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.
Keywords:Neoplasm Antigens, CD8-Positive T-Lymphocytes, HLA-DR4 Antigen, Neoplasms, Peptides, T-Cell Antigen Receptors, Animals, Mice
Source:Journal for ImmunoTherapy of Cancer
Publisher:BMJ Publishing Group
Page Range:e006001
Date:February 2023
Official Publication:https://doi.org/10.1136/jitc-2022-006001
PubMed:View item in PubMed

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