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| Item Type: | Article |
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| Title: | Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity |
| Creators Name: | Schirmer, D., Grünewald, T.G.P., Klar, R., Schmidt, O., Wohlleber, D., Rubio, R.A., Uckert, W., Thiel, U., Bohne, F., Busch, D.H., Krackhardt, A.M., Burdach, S. and Richter, G.H.S. |
| Abstract: | Pediatric cancers, including Ewing sarcoma (ES), are only weakly immunogenic and the tumor-patients' immune system often is devoid of effector T cells for tumor elimination. Based on expression profiling technology, targetable tumor-associated antigens (TAA) are identified and exploited for engineered T-cell therapy. Here, the specific recognition and lytic potential of transgenic allo-restricted CD8(+) T cells, directed against the ES-associated antigen 6-transmembrane epithelial antigen of the prostate 1 (STEAP1), was examined. Following repetitive STEAP1(130) peptide-driven stimulations with HLA-A*02:01(+) dendritic cells (DC), allo-restricted HLA-A*02:01(-) CD8(+) T cells were sorted with HLA-A*02:01/peptide multimers and expanded by limiting dilution. After functional analysis of suitable T cell clones via ELISpot, flow cytometry and xCELLigence assay, T cell receptors' (TCR) {alpha}- and {beta}-chains were identified, cloned into retroviral vectors, codon optimized, transfected into HLA-A*02:01(-) primary T cell populations and tested again for specificity and lytic capacity in vitro and in a Rag2(-/-){gamma}c(-/-) mouse model. Initially generated transgenic T cells specifically recognized STEAP1(130)-pulsed or transfected cells in the context of HLA-A*02:01 with minimal cross-reactivity as determined by specific interferon-{gamma} (IFN{gamma}) release, lysed cells and inhibited growth of HLA-A*02:01(+) ES lines more effectively than HLA-A*02:01(-) ES lines. In vivo tumor growth was inhibited more effectively with transgenic STEAP1(130)-specific T cells than with unspecific T cells. Our results identify TCRs capable of recognizing and inhibiting growth of STEAP1-expressing HLA-A*02:01(+) ES cells in vitro and in vivo in a highly restricted manner. As STEAP1 is overexpressed in a wide variety of cancers, we anticipate these STEAP1-specific TCRs to be potentially useful for immunotherapy of other STEAP1-expressing tumors. |
| Keywords: | Allo-Restricted T Cells, Ewing Sarcoma, STEAP1, TCR-Transgenic T Cells, Animals, Mice |
| Source: | OncoImmunology |
| ISSN: | 2162-402X |
| Publisher: | Taylor & Francis |
| Volume: | 5 |
| Number: | 6 |
| Page Range: | e1175795 |
| Date: | 25 April 2016 |
| Additional Information: | Copyright © 2016 Taylor & Francis Group, LLC |
| Official Publication: | https://doi.org/10.1080/2162402X.2016.1175795 |
| External Fulltext: | View full text on PubMed Central |
| PubMed: | View item in PubMed |
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