Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy.
| Title: | Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy. |
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| Authors: | Dolton G; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Rius C; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Wall A; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Szomolay B; Systems Immunology Research Institute, Cardiff, Wales CF14 4XN, UK.; Bianchi V; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Galloway SAE; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Hasan MS; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Morin T; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Caillaud ME; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Thomas HL; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Theaker S; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Tan LR; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Fuller A; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Topley K; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Legut M; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Attaf M; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Hopkins JR; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Behiry E; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Zabkiewicz J; Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Alvares C; Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Lloyd A; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Rogers A; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Henley P; Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Fegan C; Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Ottmann O; Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Man S; Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Crowther MD; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK; National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.; Donia M; National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.; Svane IM; National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.; Cole DK; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Brown PE; The Zeeman Institute, University of Warwick, Coventry CV4 7AL, UK.; Rizkallah P; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK.; Sewell AK; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK; Systems Immunology Research Institute, Cardiff, Wales CF14 4XN, UK. Electronic address: sewellak@cardiff.ac.uk. |
| Source: | Cell [Cell] 2023 Aug 03; Vol. 186 (16), pp. 3333-3349.e27. Date of Electronic Publication: 2023 Jul 24. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE |
| Imprint Name(s): | Publication: Cambridge, Ma : Cell Press; Original Publication: Cambridge, MIT Press. |
| MeSH Terms: | Antigens, Neoplasm*/metabolism ; Neoplasms*/immunology ; Neoplasms*/therapy ; Receptors, Antigen, T-Cell*/metabolism ; Proteomics*; Epitopes ; Immunotherapy ; Lymphocytes, Tumor-Infiltrating |
| Abstract: | The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A∗02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.; (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests The authors have patents granted and pending on T cell recognition of cancer via Melan A, BST2, and/or IMP2. |
| Comments: | Comment in: Cell Res. 2024 Jan;34(1):5-6. doi: 10.1038/s41422-023-00871-7.. (PMID: 37666977) |
| Grant Information: | HRG-16-1318 United Kingdom HCRW_ HCRW_; HRG-20-1724(P) United Kingdom HCRW_ HCRW_; 220295/Z/20/Z United Kingdom WT_ Wellcome Trust; BB/H001085/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council |
| Contributed Indexing: | Keywords: HLA class I; T cell receptor; TCR; TCR-T; TIL therapy; TILs; cancer immunotherapy; peptide-HLA; tumor-infiltrating lymphocytes |
| Molecular Sequence: | ClinicalTrials.gov NCT00937625 |
| Substance Nomenclature: | 0 (Antigens, Neoplasm); 0 (Epitopes); 0 (Receptors, Antigen, T-Cell) |
| Entry Date(s): | Date Created: 20230725 Date Completed: 20230808 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.cell.2023.06.020 |
| PMID: | 37490916 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't