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Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires
SIMPLE SUMMARY: T cell-based immunotherapy has achieved remarkable clinical responses in patients with cancer. Neoepitope-specific T cells can specifically recognize mutated tumor cells and have led to tumor regression in mouse models and clinical studies. However, isolating neoepitope-specific T ce...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998067/ https://www.ncbi.nlm.nih.gov/pubmed/35406613 http://dx.doi.org/10.3390/cancers14071842 |
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author | Grunert, Corinna Willimsky, Gerald Peuker, Caroline Anna Rhein, Simone Hansmann, Leo Blankenstein, Thomas Blanc, Eric Beule, Dieter Keller, Ulrich Pezzutto, Antonio Busse, Antonia |
author_facet | Grunert, Corinna Willimsky, Gerald Peuker, Caroline Anna Rhein, Simone Hansmann, Leo Blankenstein, Thomas Blanc, Eric Beule, Dieter Keller, Ulrich Pezzutto, Antonio Busse, Antonia |
author_sort | Grunert, Corinna |
collection | PubMed |
description | SIMPLE SUMMARY: T cell-based immunotherapy has achieved remarkable clinical responses in patients with cancer. Neoepitope-specific T cells can specifically recognize mutated tumor cells and have led to tumor regression in mouse models and clinical studies. However, isolating neoepitope-specific T cell receptors (TCRs) from the patients’ own repertoire has shown limited success. Sourcing T cell repertoires, other than the patients’ own, has certain advantages: the availability of larger amounts of blood from healthy donors, circumventing tumor-related immunosuppression in patients, and including different donors to broaden the pool of specific T cells. Here, for the first time, a side-by-side comparison of three different TCR donor repertoires, including patients and HLA-matched allogenic healthy human repertoires, as well as repertoires of transgenic mice, is performed. Our results support recent studies that using not only healthy donor T cell repertoires, but also transgenic mice might be a viable strategy for isolating TCRs with known specificity directed against neoantigens for adoptive T cell therapy. ABSTRACT: (1) Background: Mutation-specific T cell receptor (TCR)-based adoptive T cell therapy represents a truly tumor-specific immunotherapeutic strategy. However, isolating neoepitope-specific TCRs remains a challenge. (2) Methods: We investigated, side by side, different TCR repertoires—patients’ peripheral lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs), PBLs of healthy donors, and a humanized mouse model—to isolate neoepitope-specific TCRs against eight neoepitope candidates from a colon cancer and an ovarian cancer patient. Neoepitope candidates were used to stimulate T cells from different repertoires in vitro to generate neoepitope-specific T cells and isolate the specific TCRs. (3) Results: We isolated six TCRs from healthy donors, directed against four neoepitope candidates and one TCR from the murine T cell repertoire. Endogenous processing of one neoepitope, for which we isolated one TCR from both human and mouse-derived repertoires, could be shown. No neoepitope-specific TCR could be generated from the patients’ own repertoire. (4) Conclusion: Our data indicate that successful isolation of neoepitope-specific TCRs depends on various factors such as the heathy donor’s TCR repertoire or the presence of a tumor microenvironment allowing neoepitope-specific immune responses of the host. We show the advantage and feasibility of using healthy donor repertoires and humanized mouse TCR repertoires to generate mutation-specific TCRs with different specificities, especially in a setting when the availability of patient material is limited. |
format | Online Article Text |
id | pubmed-8998067 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89980672022-04-12 Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires Grunert, Corinna Willimsky, Gerald Peuker, Caroline Anna Rhein, Simone Hansmann, Leo Blankenstein, Thomas Blanc, Eric Beule, Dieter Keller, Ulrich Pezzutto, Antonio Busse, Antonia Cancers (Basel) Article SIMPLE SUMMARY: T cell-based immunotherapy has achieved remarkable clinical responses in patients with cancer. Neoepitope-specific T cells can specifically recognize mutated tumor cells and have led to tumor regression in mouse models and clinical studies. However, isolating neoepitope-specific T cell receptors (TCRs) from the patients’ own repertoire has shown limited success. Sourcing T cell repertoires, other than the patients’ own, has certain advantages: the availability of larger amounts of blood from healthy donors, circumventing tumor-related immunosuppression in patients, and including different donors to broaden the pool of specific T cells. Here, for the first time, a side-by-side comparison of three different TCR donor repertoires, including patients and HLA-matched allogenic healthy human repertoires, as well as repertoires of transgenic mice, is performed. Our results support recent studies that using not only healthy donor T cell repertoires, but also transgenic mice might be a viable strategy for isolating TCRs with known specificity directed against neoantigens for adoptive T cell therapy. ABSTRACT: (1) Background: Mutation-specific T cell receptor (TCR)-based adoptive T cell therapy represents a truly tumor-specific immunotherapeutic strategy. However, isolating neoepitope-specific TCRs remains a challenge. (2) Methods: We investigated, side by side, different TCR repertoires—patients’ peripheral lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs), PBLs of healthy donors, and a humanized mouse model—to isolate neoepitope-specific TCRs against eight neoepitope candidates from a colon cancer and an ovarian cancer patient. Neoepitope candidates were used to stimulate T cells from different repertoires in vitro to generate neoepitope-specific T cells and isolate the specific TCRs. (3) Results: We isolated six TCRs from healthy donors, directed against four neoepitope candidates and one TCR from the murine T cell repertoire. Endogenous processing of one neoepitope, for which we isolated one TCR from both human and mouse-derived repertoires, could be shown. No neoepitope-specific TCR could be generated from the patients’ own repertoire. (4) Conclusion: Our data indicate that successful isolation of neoepitope-specific TCRs depends on various factors such as the heathy donor’s TCR repertoire or the presence of a tumor microenvironment allowing neoepitope-specific immune responses of the host. We show the advantage and feasibility of using healthy donor repertoires and humanized mouse TCR repertoires to generate mutation-specific TCRs with different specificities, especially in a setting when the availability of patient material is limited. MDPI 2022-04-06 /pmc/articles/PMC8998067/ /pubmed/35406613 http://dx.doi.org/10.3390/cancers14071842 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Grunert, Corinna Willimsky, Gerald Peuker, Caroline Anna Rhein, Simone Hansmann, Leo Blankenstein, Thomas Blanc, Eric Beule, Dieter Keller, Ulrich Pezzutto, Antonio Busse, Antonia Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires |
title | Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires |
title_full | Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires |
title_fullStr | Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires |
title_full_unstemmed | Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires |
title_short | Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires |
title_sort | isolation of neoantigen-specific human t cell receptors from different human and murine repertoires |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998067/ https://www.ncbi.nlm.nih.gov/pubmed/35406613 http://dx.doi.org/10.3390/cancers14071842 |
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