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
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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2023-06
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Language
en
Pages
11
13486-13496
13486-13496
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Cancer Medicine, Volume 12, issue 12
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.Description
Funding Information: We thank Tamás Bazsinka for technical support and Finnish Medical Foundation, Foundation for Pediatric Research, the MD PhD program of the Faculty of Medicine of the University of Helsinki, Waldemar von Frenckell Foundation, Liv och Hälsa Foundation and Helsinki University Library for their financial support. Open access funded by Helsinki University Library. Funding Information: This study was funded by impartial foundations and research programs; we did not receive any corporate funding. Grants from Finnish Medical Foundation (grant no. 4115), Foundation for Pediatric Research, and the MD PhD program of the Faculty of Medicine of the University of Helsinki were used to pay for human resources. The grants from Waldemar von Frenckell Foundation, Liv och Hälsa Foundation, and Foundation for Pediatric Research facilitated material and sequencing costs for the study. Publisher Copyright: © 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Keywords
cancer biology, immunology, mutations, vaccine
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Citation
Mattila, J, Sormunen, S, Heikkilä, N, Mattila, I P, Saramäki, J & Arstila, T P 2023, ' 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, vol. 12, no. 12, pp. 13486-13496 . https://doi.org/10.1002/cam4.6002