Immunogenicity of non-canonical HLA-I tumor ligands identified through proteogenomics
Abstract Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from non-canonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the immunogenicity of nonC tumor HLA-I ligands (nonC-TL) to better understand their contribution to cancer immunosurveillance and their therapeutic applicability. Using proteogenomics, we identified 517 nonC-TL from 9 patients with melanoma, gynecological, and head and neck cancer. We found no recognition of the 507 nonC-TL tested by autologousex vivoexpanded tumor reactive T-cell cultures while the same cultures demonstrated reactivity to mutated, cancer-germline, or melanocyte differentiation antigens. However,in vitrosensitization of donor peripheral blood lymphocytes against 170 selected nonC-TL, led to the identification of T-cell receptors (TCRs) specific to three nonC-TL, two of which mapped to the 5’ UTR regions of HOXC13 and ZKSCAN1, and one mapping to a non-coding spliced variant of C5orf22C. T cells targeting these nonC-TL recognized cancer cell lines naturally presenting their corresponding antigens. Expression of the three immunogenic nonC-TL was shared across tumor types and barely or not detected in normal cells. Our findings predict a limited contribution of nonC-TL to cancer immunosurveillance but demonstrate they may be attractive novel targets for widely applicable immunotherapies..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 23. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lozano-Rabella, Maria [VerfasserIn] |
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| doi: |
10.1101/2022.11.07.514886 |
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| PPN (Katalog-ID): |
XBI037812580 |
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| 520 | |a Abstract Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from non-canonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the immunogenicity of nonC tumor HLA-I ligands (nonC-TL) to better understand their contribution to cancer immunosurveillance and their therapeutic applicability. Using proteogenomics, we identified 517 nonC-TL from 9 patients with melanoma, gynecological, and head and neck cancer. We found no recognition of the 507 nonC-TL tested by autologousex vivoexpanded tumor reactive T-cell cultures while the same cultures demonstrated reactivity to mutated, cancer-germline, or melanocyte differentiation antigens. However,in vitrosensitization of donor peripheral blood lymphocytes against 170 selected nonC-TL, led to the identification of T-cell receptors (TCRs) specific to three nonC-TL, two of which mapped to the 5’ UTR regions of HOXC13 and ZKSCAN1, and one mapping to a non-coding spliced variant of C5orf22C. T cells targeting these nonC-TL recognized cancer cell lines naturally presenting their corresponding antigens. Expression of the three immunogenic nonC-TL was shared across tumor types and barely or not detected in normal cells. Our findings predict a limited contribution of nonC-TL to cancer immunosurveillance but demonstrate they may be attractive novel targets for widely applicable immunotherapies. | ||
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| 700 | 1 | |a Palomero, Jara |e verfasserin |4 aut | |
| 700 | 1 | |a Yuste-Estevanez, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Erhard, Florian |e verfasserin |0 (orcid)0000-0002-3574-6983 |4 aut | |
| 700 | 1 | |a Martín-Liberal, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a de Olza, Maria Ochoa |e verfasserin |4 aut | |
| 700 | 1 | |a Matos, Ignacio |e verfasserin |4 aut | |
| 700 | 1 | |a Gartner, Jared J. |e verfasserin |4 aut | |
| 700 | 1 | |a Ghosh, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Canals, Francesc |e verfasserin |4 aut | |
| 700 | 1 | |a Vidal, August |e verfasserin |4 aut | |
| 700 | 1 | |a Piulats, Josep Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Matias-Guiu, Xavier |e verfasserin |4 aut | |
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| 700 | 1 | |a Schlosser, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Gros, Alena |e verfasserin |4 aut | |
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