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LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager
Colorectal cancer (CRC) is one of the most common cancers worldwide and demands more effective treatments. We sought to identify tumor selective CRC antigens and their therapeutic potential for cytotoxic T-cell targeting by transcriptomic and immunohistochemical analysis. LY6G6D was identified as a...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9493073/ https://www.ncbi.nlm.nih.gov/pubmed/36159851 http://dx.doi.org/10.3389/fimmu.2022.1008764 |
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author | Corrales, Leticia Hipp, Susanne Martin, Katharina Sabarth, Nicolas Tirapu, Iñigo Fuchs, Klaus Thaler, Barbara Walterskirchen, Christian Bauer, Kathrin Fabits, Markus Bergmann, Michael Binder, Carina Chetta, Paolo ML. Vogt, Anne B. Adam, Paul J. |
author_facet | Corrales, Leticia Hipp, Susanne Martin, Katharina Sabarth, Nicolas Tirapu, Iñigo Fuchs, Klaus Thaler, Barbara Walterskirchen, Christian Bauer, Kathrin Fabits, Markus Bergmann, Michael Binder, Carina Chetta, Paolo ML. Vogt, Anne B. Adam, Paul J. |
author_sort | Corrales, Leticia |
collection | PubMed |
description | Colorectal cancer (CRC) is one of the most common cancers worldwide and demands more effective treatments. We sought to identify tumor selective CRC antigens and their therapeutic potential for cytotoxic T-cell targeting by transcriptomic and immunohistochemical analysis. LY6G6D was identified as a tumor selectively expressed CRC antigen, mainly in the microsatellite stable (MSS) subtype. A specific anti LY6G6D/CD3 T cell engager (TcE) was generated and demonstrated potent tumor cell killing and T cell activation in vitro. Ex vivo treatment of primary patient-derived CRC tumor slice cultures with the LY6G6D/CD3 TcE led to IFNγ secretion in LY6G6D positive tumor samples. In vivo, LY6G6D/CD3 TcE monotherapy demonstrated tumor regressions in pre-clinical mouse models of engrafted human CRC tumor cells and PBMCs. Lastly, 2D and 3D cocultures of LY6G6D positive and negative cells were used to explore the bystander killing of LY6G6D negative cells after specific activation of T cells by LY6G6D positive cells. LY6G6D/CD3 TcE treatment was shown to lyse target negative cells in the vicinity of target positive cells through a combined effect of IFNγ, TNFα and Fas/FasL. In summary, LY6G6D was identified as a selectively expressed CRC antigen that can be utilized to potently re-direct and activate cytotoxic T-cells to lyse LY6G6D expressing CRC using a TcE. This effect can be spread to target negative neighboring tumor cells, potentially leading to improved therapeutic efficacy. |
format | Online Article Text |
id | pubmed-9493073 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94930732022-09-23 LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager Corrales, Leticia Hipp, Susanne Martin, Katharina Sabarth, Nicolas Tirapu, Iñigo Fuchs, Klaus Thaler, Barbara Walterskirchen, Christian Bauer, Kathrin Fabits, Markus Bergmann, Michael Binder, Carina Chetta, Paolo ML. Vogt, Anne B. Adam, Paul J. Front Immunol Immunology Colorectal cancer (CRC) is one of the most common cancers worldwide and demands more effective treatments. We sought to identify tumor selective CRC antigens and their therapeutic potential for cytotoxic T-cell targeting by transcriptomic and immunohistochemical analysis. LY6G6D was identified as a tumor selectively expressed CRC antigen, mainly in the microsatellite stable (MSS) subtype. A specific anti LY6G6D/CD3 T cell engager (TcE) was generated and demonstrated potent tumor cell killing and T cell activation in vitro. Ex vivo treatment of primary patient-derived CRC tumor slice cultures with the LY6G6D/CD3 TcE led to IFNγ secretion in LY6G6D positive tumor samples. In vivo, LY6G6D/CD3 TcE monotherapy demonstrated tumor regressions in pre-clinical mouse models of engrafted human CRC tumor cells and PBMCs. Lastly, 2D and 3D cocultures of LY6G6D positive and negative cells were used to explore the bystander killing of LY6G6D negative cells after specific activation of T cells by LY6G6D positive cells. LY6G6D/CD3 TcE treatment was shown to lyse target negative cells in the vicinity of target positive cells through a combined effect of IFNγ, TNFα and Fas/FasL. In summary, LY6G6D was identified as a selectively expressed CRC antigen that can be utilized to potently re-direct and activate cytotoxic T-cells to lyse LY6G6D expressing CRC using a TcE. This effect can be spread to target negative neighboring tumor cells, potentially leading to improved therapeutic efficacy. Frontiers Media S.A. 2022-09-08 /pmc/articles/PMC9493073/ /pubmed/36159851 http://dx.doi.org/10.3389/fimmu.2022.1008764 Text en Copyright © 2022 Corrales, Hipp, Martin, Sabarth, Tirapu, Fuchs, Thaler, Walterskirchen, Bauer, Fabits, Bergmann, Binder, Chetta, Vogt and Adam https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Corrales, Leticia Hipp, Susanne Martin, Katharina Sabarth, Nicolas Tirapu, Iñigo Fuchs, Klaus Thaler, Barbara Walterskirchen, Christian Bauer, Kathrin Fabits, Markus Bergmann, Michael Binder, Carina Chetta, Paolo ML. Vogt, Anne B. Adam, Paul J. LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager |
title | LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager |
title_full | LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager |
title_fullStr | LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager |
title_full_unstemmed | LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager |
title_short | LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager |
title_sort | ly6g6d is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic t-cell response by a t-cell engager |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9493073/ https://www.ncbi.nlm.nih.gov/pubmed/36159851 http://dx.doi.org/10.3389/fimmu.2022.1008764 |
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