| Reference | ||
|---|---|---|
| Reference Type | Literature | IEDB_Reference:1036933 |
| Title | Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen. | |
| Authors | Daichao Wu; D Travis Gallagher; Ragul Gowthaman; Brian G Pierce; Roy A Mariuzza | |
| Affiliations | W.M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD, 20850, USA; Department of Histology and Embryology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, 20742, USA; National Institute of Standards and Technology, Gaitherburg, MD, 20899, USA; W.M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD, 20850, USA. rmariuzz@umd.edu; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, 20742, USA. rmariuzz@umd.edu. | |
| Journal | Nat Commun | |
| Year | 2020 | |
| Abstract | Adoptive cell therapy (ACT) with tumor-specific T cells can mediate cancer regression. The main target of tumor-specific T cells are neoantigens arising from mutations in self-proteins. Although the majority of cancer neoantigens are unique to each patient, and therefore not broadly useful for ACT, some are shared. We studied oligoclonal T-cell receptors (TCRs) that recognize a shared neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by HLA-A2. Here we report structures of wild-type and mutant p53-HLA-A2 ligands, as well as structures of three tumor-specific TCRs bound to p53R175H-HLA-A2. These structures reveal how a driver mutation in p53 rendered a self-peptide visible to T cells. The TCRs employ structurally distinct strategies that are highly focused on the mutation to discriminate between mutant and wild-type p53. The TCR-p53R175H-HLA-A2 complexes provide a framework for designing TCRs to improve potency for ACT without sacrificing specificity. | |
| Curation Last Updated | 2024-08-01 19:23:06 | |
| Epitope | ||
|---|---|---|
| Epitope ID | 1125066 | IEDB_epitope:1125066 |
| Chemical Type | Linear peptide | |
| Linear Sequence | HMTEVVRHC | |
| Epitope Reference Details | ||
|---|---|---|
| Epitope Structure Defines | Exact Epitope | |
| Epitope Name | p53 R175H | |
| Location of Data in Reference | Methods | |
| Epitope Related Object | ||
|---|---|---|
| Related Object Type | in-frame neo-epitope | |
| Chemical Type | Linear peptide | |
| Linear Sequence | HMTEVVRRC | |
| Source Molecule Name | Cellular tumor antigen p53 | |
| Source Organism | Homo sapiens (human) | |
| Starting Position | 168 | |
| Ending Position | 176 | |
| Immunization | ||
|---|---|---|
| Host Organism | Homo sapiens (human) | |
| Host Details | ||
|---|---|---|
| Host Geolocation | contiguous United States of America [ID: GAZ_00003937] | |
| 1st In Vivo Process | ||
|---|---|---|
| In Vivo Process Type | Occurrence of cancer | |
| Disease State | colorectal cancer | |
| Disease Stage | Cancer Stage IV; | NCIT:C27971 |
| Immunization Comments | ||
|---|---|---|
| Immunization Comments | The TCR was isolated by screening TILs from patients with metastatic colorectal cancer for reactivity towards mutated p53 neoantigens as described in the cited references: Malekzadeh et al. (2019) J Clin Invest 129(3): 1109-1114 [PMID: 30714987] and Lo et al. (2019) Cancer Immunol Res 7(4): 534-543 [PMID: 30709841]. Pulmonary metastases were resected for generation of TIL. Identification of p53 neoantigen-specific TCRs was achieved by co-culturing TIL with p53 neoepitopes and single-cell sorting 41BB expressing T cells or epitope/HLA-A*0201 tetramers were used to stain T cells in TIL. RNA was isolated and used to identify paired full-length TCRα/β sequences. | |
| T Cell Assay | ||
|---|---|---|
| Qualitative Measurement | Positive | |
| Method/Technique | binding assay | |
| Measurement of | off rate | |
| Assay Type Units | 1/s | |
| Measurement Details | ||
|---|---|---|
| Quantitative measurement | 0.032 | |
| Assayed TCR Molecule | ||
|---|---|---|
| Assayed TCR Molecule Name | 12-6 | |
| Assayed TCR Molecule Chain 1 Type | Alpha | |
| Assayed TCR Molecule Chain 2 Type | Beta | |
| Assayed TCR Object | ||
|---|---|---|
| Chemical Type | Multi-Chain protein | |
| Chain 1 Accession Name | Chain D, T-cell receptor 12-6, alfa chain | |
| Source Organism | Homo sapiens (human) | |
| Molecule Name | 12-6 | |
| Chain 2 Name | Chain E, TCR 12-6, beta chain | |
| Source Organism | Homo sapiens (human) | |
| MHC Allele | ||
|---|---|---|
| MHC Allele Name | HLA-A*02:01 | |
| MHC Evidence Code | MHC binding assay | |
| Antigen | ||
|---|---|---|
| Epitope Relation | Epitope | |
| Chemical Type | Linear peptide | |
| Linear Sequence | HMTEVVRHC | |
| Assay Reference Details | ||
|---|---|---|
| Assay Comments by IEDB Curator | The binding kinetics for the interaction between the 12-6 TCR and the epitope/HLA-A*02:01 complex were determined by SPR. No apparent interaction between any of the TCR and wild-type p53/HLA-A*02:01 was detected, even after injecting high concentrations of TCR. | |
| Location of Assay Data in Reference | Figure 1 | |