Molecular mechanism of phosphopeptide neoantigen immunogenicity
Abstract Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747–755...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39425-1 |
| _version_ | 1797769450456350720 |
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| author | Yury Patskovsky Aswin Natarajan Larysa Patskovska Samantha Nyovanie Bishnu Joshi Benjamin Morin Christine Brittsan Olivia Huber Samuel Gordon Xavier Michelet Florian Schmitzberger Robert B. Stein Mark A. Findeis Andy Hurwitz Marc Van Dijk Eleni Chantzoura Alvaro S. Yague Daniel Pollack Smith Jennifer S. Buell Dennis Underwood Michelle Krogsgaard |
| author_facet | Yury Patskovsky Aswin Natarajan Larysa Patskovska Samantha Nyovanie Bishnu Joshi Benjamin Morin Christine Brittsan Olivia Huber Samuel Gordon Xavier Michelet Florian Schmitzberger Robert B. Stein Mark A. Findeis Andy Hurwitz Marc Van Dijk Eleni Chantzoura Alvaro S. Yague Daniel Pollack Smith Jennifer S. Buell Dennis Underwood Michelle Krogsgaard |
| author_sort | Yury Patskovsky |
| collection | DOAJ |
| description | Abstract Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747–755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization. |
| first_indexed | 2024-03-12T21:08:12Z |
| format | Article |
| id | doaj.art-90c3efa5a9bc4657b99b525a37d24797 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T21:08:12Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-90c3efa5a9bc4657b99b525a37d247972023-07-30T11:19:37ZengNature PortfolioNature Communications2041-17232023-06-0114111810.1038/s41467-023-39425-1Molecular mechanism of phosphopeptide neoantigen immunogenicityYury Patskovsky0Aswin Natarajan1Larysa Patskovska2Samantha Nyovanie3Bishnu Joshi4Benjamin Morin5Christine Brittsan6Olivia Huber7Samuel Gordon8Xavier Michelet9Florian Schmitzberger10Robert B. Stein11Mark A. Findeis12Andy Hurwitz13Marc Van Dijk14Eleni Chantzoura15Alvaro S. Yague16Daniel Pollack Smith17Jennifer S. Buell18Dennis Underwood19Michelle Krogsgaard20Department of Pathology, New York University Grossman School of MedicineDepartment of Pathology, New York University Grossman School of MedicineDepartment of Pathology, New York University Grossman School of MedicineDepartment of Pathology, New York University Grossman School of MedicineAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusAgenusDepartment of Pathology, New York University Grossman School of MedicineAbstract Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747–755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.https://doi.org/10.1038/s41467-023-39425-1 |
| spellingShingle | Yury Patskovsky Aswin Natarajan Larysa Patskovska Samantha Nyovanie Bishnu Joshi Benjamin Morin Christine Brittsan Olivia Huber Samuel Gordon Xavier Michelet Florian Schmitzberger Robert B. Stein Mark A. Findeis Andy Hurwitz Marc Van Dijk Eleni Chantzoura Alvaro S. Yague Daniel Pollack Smith Jennifer S. Buell Dennis Underwood Michelle Krogsgaard Molecular mechanism of phosphopeptide neoantigen immunogenicity Nature Communications |
| title | Molecular mechanism of phosphopeptide neoantigen immunogenicity |
| title_full | Molecular mechanism of phosphopeptide neoantigen immunogenicity |
| title_fullStr | Molecular mechanism of phosphopeptide neoantigen immunogenicity |
| title_full_unstemmed | Molecular mechanism of phosphopeptide neoantigen immunogenicity |
| title_short | Molecular mechanism of phosphopeptide neoantigen immunogenicity |
| title_sort | molecular mechanism of phosphopeptide neoantigen immunogenicity |
| url | https://doi.org/10.1038/s41467-023-39425-1 |
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