Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma
<jats:p>While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or...
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| Format: | Article |
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Frontiers Media SA
2022
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| Online Access: | https://hdl.handle.net/1721.1/143653 |
| _version_ | 1826188273962188800 |
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| author | Grace, Beth E. Backlund, Coralie M. Morgan, Duncan M. Kang, Byong H. Singh, Nishant K. Huisman, Brooke D. Rappazzo, C. Garrett Moynihan, Kelly D. Maiorino, Laura Dobson, Connor S. Kyung, Taeyoon Gordon, Khloe S. Holec, Patrick V. Mbah, Overbeck C. Takou Garafola, Daniel Wu, Shengwei Love, J. Christopher Wittrup, K. Dane Irvine, Darrell J. Birnbaum, Michael E. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Grace, Beth E. Backlund, Coralie M. Morgan, Duncan M. Kang, Byong H. Singh, Nishant K. Huisman, Brooke D. Rappazzo, C. Garrett Moynihan, Kelly D. Maiorino, Laura Dobson, Connor S. Kyung, Taeyoon Gordon, Khloe S. Holec, Patrick V. Mbah, Overbeck C. Takou Garafola, Daniel Wu, Shengwei Love, J. Christopher Wittrup, K. Dane Irvine, Darrell J. Birnbaum, Michael E. |
| author_sort | Grace, Beth E. |
| collection | MIT |
| description | <jats:p>While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8<jats:sup>+</jats:sup> T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response <jats:italic>in vivo</jats:italic>, engineered antigen mimotopes induced a significant expansion of CD8<jats:sup>+</jats:sup> T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells <jats:italic>in vivo</jats:italic> yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.</jats:p> |
| first_indexed | 2024-09-23T07:57:10Z |
| format | Article |
| id | mit-1721.1/143653 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T07:57:10Z |
| publishDate | 2022 |
| publisher | Frontiers Media SA |
| record_format | dspace |
| spelling | mit-1721.1/1436532023-07-10T19:29:42Z Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma Grace, Beth E. Backlund, Coralie M. Morgan, Duncan M. Kang, Byong H. Singh, Nishant K. Huisman, Brooke D. Rappazzo, C. Garrett Moynihan, Kelly D. Maiorino, Laura Dobson, Connor S. Kyung, Taeyoon Gordon, Khloe S. Holec, Patrick V. Mbah, Overbeck C. Takou Garafola, Daniel Wu, Shengwei Love, J. Christopher Wittrup, K. Dane Irvine, Darrell J. Birnbaum, Michael E. Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Chemical Engineering Ragon Institute of MGH, MIT and Harvard <jats:p>While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8<jats:sup>+</jats:sup> T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response <jats:italic>in vivo</jats:italic>, engineered antigen mimotopes induced a significant expansion of CD8<jats:sup>+</jats:sup> T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells <jats:italic>in vivo</jats:italic> yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.</jats:p> 2022-07-11T18:11:14Z 2022-07-11T18:11:14Z 2022-06-23 Article http://purl.org/eprint/type/JournalArticle 1664-3224 https://hdl.handle.net/1721.1/143653 Grace, Beth E., Backlund, Coralie M., Morgan, Duncan M., Kang, Byong H., Singh, Nishant K. et al. 2022. "Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma." Frontiers in Immunology, 13. 10.3389/fimmu.2022.886683 Frontiers in Immunology Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Frontiers Media SA Frontiers |
| spellingShingle | Grace, Beth E. Backlund, Coralie M. Morgan, Duncan M. Kang, Byong H. Singh, Nishant K. Huisman, Brooke D. Rappazzo, C. Garrett Moynihan, Kelly D. Maiorino, Laura Dobson, Connor S. Kyung, Taeyoon Gordon, Khloe S. Holec, Patrick V. Mbah, Overbeck C. Takou Garafola, Daniel Wu, Shengwei Love, J. Christopher Wittrup, K. Dane Irvine, Darrell J. Birnbaum, Michael E. Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma |
| title | Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma |
| title_full | Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma |
| title_fullStr | Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma |
| title_full_unstemmed | Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma |
| title_short | Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma |
| title_sort | identification of highly cross reactive mimotopes for a public t cell response in murine melanoma |
| url | https://hdl.handle.net/1721.1/143653 |
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