Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens
Abstract Background The number of mutations in cancer cells is an important predictor of a positive response to cancer immunotherapy. It has been suggested that the neoantigens produced by these mutations are more immunogenic than nonmutated tumor antigens, which are likely to be protected by immuno...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-06-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.6002 |
| _version_ | 1797775571228295168 |
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| author | Joonatan Mattila Silja Sormunen Nelli Heikkilä Ilkka P. Mattila Jari Saramäki T. Petteri Arstila |
| author_facet | Joonatan Mattila Silja Sormunen Nelli Heikkilä Ilkka P. Mattila Jari Saramäki T. Petteri Arstila |
| author_sort | Joonatan Mattila |
| collection | DOAJ |
| description | Abstract Background The number of mutations in cancer cells is an important predictor of a positive response to cancer immunotherapy. It has been suggested that the neoantigens produced by these mutations are more immunogenic than nonmutated tumor antigens, which are likely to be protected by immunological tolerance. However, the mechanisms of tolerance as regards tumor antigens are incompletely understood. Methods Here, we have analyzed the impact of thymic negative selection on shared T‐cell receptor (TCR) repertoire associated with the recognition of either mutated or nonmutated tumor antigens by comparing previously known TCR—antigen—pairs to TCR repertoires of 21 immunologically healthy individuals. Results Our results show that TCRα chains associated with either type of tumor antigens are readily generated in the thymus, at a frequency similar to TCRα chains associated with nonself. In the peripheral repertoire, the relative clone size of nonself‐associated chains is higher than that of the tumor antigens, but importantly, there is no difference between TCRα chains associated with mutated or nonmutated tumor antigens. Conclusion This suggests that the tolerance mechanisms protecting nonmutated tumor antigens are non‐deletional and therefore potentially reversible. As unmutated antigens are, unlike mutations, shared by a large number of patients, they may offer advantages in designing immunological approaches to cancer treatment. |
| first_indexed | 2024-03-12T22:37:33Z |
| format | Article |
| id | doaj.art-a1fd196e9f9b4512b675514b1c392ed5 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-03-12T22:37:33Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-a1fd196e9f9b4512b675514b1c392ed52023-07-21T11:20:58ZengWileyCancer Medicine2045-76342023-06-011212134861349610.1002/cam4.6002Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigensJoonatan Mattila0Silja Sormunen1Nelli Heikkilä2Ilkka P. Mattila3Jari Saramäki4T. Petteri Arstila5Research Programs Unit, Translational Immunology, Haartmaninkatu 3 (PL 21) 00014, and Medicum University of Helsinki Helsinki FinlandDepartment of Computer Science Aalto University Espoo FinlandResearch Programs Unit, Translational Immunology, Haartmaninkatu 3 (PL 21) 00014, and Medicum University of Helsinki Helsinki FinlandDepartment of Pediatric Cardiac and Transplantation Surgery Hospital for Children and Adolescents, Helsinki University Central Hospital Helsinki FinlandDepartment of Computer Science Aalto University Espoo FinlandResearch Programs Unit, Translational Immunology, Haartmaninkatu 3 (PL 21) 00014, and Medicum University of Helsinki Helsinki FinlandAbstract Background The number of mutations in cancer cells is an important predictor of a positive response to cancer immunotherapy. It has been suggested that the neoantigens produced by these mutations are more immunogenic than nonmutated tumor antigens, which are likely to be protected by immunological tolerance. However, the mechanisms of tolerance as regards tumor antigens are incompletely understood. Methods Here, we have analyzed the impact of thymic negative selection on shared T‐cell receptor (TCR) repertoire associated with the recognition of either mutated or nonmutated tumor antigens by comparing previously known TCR—antigen—pairs to TCR repertoires of 21 immunologically healthy individuals. Results Our results show that TCRα chains associated with either type of tumor antigens are readily generated in the thymus, at a frequency similar to TCRα chains associated with nonself. In the peripheral repertoire, the relative clone size of nonself‐associated chains is higher than that of the tumor antigens, but importantly, there is no difference between TCRα chains associated with mutated or nonmutated tumor antigens. Conclusion This suggests that the tolerance mechanisms protecting nonmutated tumor antigens are non‐deletional and therefore potentially reversible. As unmutated antigens are, unlike mutations, shared by a large number of patients, they may offer advantages in designing immunological approaches to cancer treatment.https://doi.org/10.1002/cam4.6002cancer biologyimmunologymutationsvaccine |
| spellingShingle | Joonatan Mattila Silja Sormunen Nelli Heikkilä Ilkka P. Mattila Jari Saramäki T. Petteri Arstila Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens Cancer Medicine cancer biology immunology mutations vaccine |
| title | Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens |
| title_full | Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens |
| title_fullStr | Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens |
| title_full_unstemmed | Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens |
| title_short | Analysis of thymic generation of shared T‐cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild‐type antigens |
| title_sort | analysis of thymic generation of shared t cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild type antigens |
| topic | cancer biology immunology mutations vaccine |
| url | https://doi.org/10.1002/cam4.6002 |
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