Cargando…
Enhancing Efficacy of TCR-engineered CD4(+) T Cells Via Coexpression of CD8α
Adoptive cell therapy with T cells expressing affinity-enhanced T-cell receptors (TCRs) is a promising treatment for solid tumors. Efforts are ongoing to further engineer these T cells to increase the depth and durability of clinical responses and broaden efficacy toward additional indications. In t...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10072215/ https://www.ncbi.nlm.nih.gov/pubmed/36826388 http://dx.doi.org/10.1097/CJI.0000000000000456 |
_version_ | 1785019336710160384 |
---|---|
author | Anderson, Victoria E. Brilha, Sara S. Weber, Anika M. Pachnio, Annette Wiedermann, Guy E. Dauleh, Sumaya Ahmed, Tina Pope, George R. Quinn, Laura L. Docta, Roslin Y. Quattrini, Adriano Masters, Siobhan Cartwright, Neil Viswanathan, Preetha Melchiori, Luca Rice, Louise V. Sevko, Alexandra Gueguen, Claire Saini, Manoj Tavano, Barbara Abbott, Rachel J.M. Silk, Jonathan D. Laugel, Bruno Sanderson, Joseph P. Gerry, Andrew B. |
author_facet | Anderson, Victoria E. Brilha, Sara S. Weber, Anika M. Pachnio, Annette Wiedermann, Guy E. Dauleh, Sumaya Ahmed, Tina Pope, George R. Quinn, Laura L. Docta, Roslin Y. Quattrini, Adriano Masters, Siobhan Cartwright, Neil Viswanathan, Preetha Melchiori, Luca Rice, Louise V. Sevko, Alexandra Gueguen, Claire Saini, Manoj Tavano, Barbara Abbott, Rachel J.M. Silk, Jonathan D. Laugel, Bruno Sanderson, Joseph P. Gerry, Andrew B. |
author_sort | Anderson, Victoria E. |
collection | PubMed |
description | Adoptive cell therapy with T cells expressing affinity-enhanced T-cell receptors (TCRs) is a promising treatment for solid tumors. Efforts are ongoing to further engineer these T cells to increase the depth and durability of clinical responses and broaden efficacy toward additional indications. In the present study, we investigated one such approach: T cells were transduced with a lentiviral vector to coexpress an affinity-enhanced HLA class I–restricted TCR directed against MAGE-A4 alongside a CD8α coreceptor. We hypothesized that this approach would enhance CD4(+) T-cell helper and effector functions, possibly leading to a more potent antitumor response. Activation of transduced CD4(+) T cells was measured by detecting CD40 ligand expression on the surface and cytokine and chemokine secretion from CD4(+) T cells and dendritic cells cultured with melanoma-associated antigen A4(+) tumor cells. In addition, T-cell cytotoxic activity against 3-dimensional tumor spheroids was measured. Our data demonstrated that CD4(+) T cells coexpressing the TCR and CD8α coreceptor displayed enhanced responses, including CD40 ligand expression, interferon-gamma secretion, and cytotoxic activity, along with improved dendritic cell activation. Therefore, our study supports the addition of the CD8α coreceptor to HLA class I–restricted TCR-engineered T cells to enhance CD4(+) T-cell functions, which may potentially improve the depth and durability of antitumor responses in patients. |
format | Online Article Text |
id | pubmed-10072215 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-100722152023-04-05 Enhancing Efficacy of TCR-engineered CD4(+) T Cells Via Coexpression of CD8α Anderson, Victoria E. Brilha, Sara S. Weber, Anika M. Pachnio, Annette Wiedermann, Guy E. Dauleh, Sumaya Ahmed, Tina Pope, George R. Quinn, Laura L. Docta, Roslin Y. Quattrini, Adriano Masters, Siobhan Cartwright, Neil Viswanathan, Preetha Melchiori, Luca Rice, Louise V. Sevko, Alexandra Gueguen, Claire Saini, Manoj Tavano, Barbara Abbott, Rachel J.M. Silk, Jonathan D. Laugel, Bruno Sanderson, Joseph P. Gerry, Andrew B. J Immunother Basic Studies Adoptive cell therapy with T cells expressing affinity-enhanced T-cell receptors (TCRs) is a promising treatment for solid tumors. Efforts are ongoing to further engineer these T cells to increase the depth and durability of clinical responses and broaden efficacy toward additional indications. In the present study, we investigated one such approach: T cells were transduced with a lentiviral vector to coexpress an affinity-enhanced HLA class I–restricted TCR directed against MAGE-A4 alongside a CD8α coreceptor. We hypothesized that this approach would enhance CD4(+) T-cell helper and effector functions, possibly leading to a more potent antitumor response. Activation of transduced CD4(+) T cells was measured by detecting CD40 ligand expression on the surface and cytokine and chemokine secretion from CD4(+) T cells and dendritic cells cultured with melanoma-associated antigen A4(+) tumor cells. In addition, T-cell cytotoxic activity against 3-dimensional tumor spheroids was measured. Our data demonstrated that CD4(+) T cells coexpressing the TCR and CD8α coreceptor displayed enhanced responses, including CD40 ligand expression, interferon-gamma secretion, and cytotoxic activity, along with improved dendritic cell activation. Therefore, our study supports the addition of the CD8α coreceptor to HLA class I–restricted TCR-engineered T cells to enhance CD4(+) T-cell functions, which may potentially improve the depth and durability of antitumor responses in patients. Lippincott Williams & Wilkins 2023-05 2023-02-27 /pmc/articles/PMC10072215/ /pubmed/36826388 http://dx.doi.org/10.1097/CJI.0000000000000456 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Basic Studies Anderson, Victoria E. Brilha, Sara S. Weber, Anika M. Pachnio, Annette Wiedermann, Guy E. Dauleh, Sumaya Ahmed, Tina Pope, George R. Quinn, Laura L. Docta, Roslin Y. Quattrini, Adriano Masters, Siobhan Cartwright, Neil Viswanathan, Preetha Melchiori, Luca Rice, Louise V. Sevko, Alexandra Gueguen, Claire Saini, Manoj Tavano, Barbara Abbott, Rachel J.M. Silk, Jonathan D. Laugel, Bruno Sanderson, Joseph P. Gerry, Andrew B. Enhancing Efficacy of TCR-engineered CD4(+) T Cells Via Coexpression of CD8α |
title | Enhancing Efficacy of TCR-engineered CD4(+) T Cells Via Coexpression of CD8α |
title_full | Enhancing Efficacy of TCR-engineered CD4(+) T Cells Via Coexpression of CD8α |
title_fullStr | Enhancing Efficacy of TCR-engineered CD4(+) T Cells Via Coexpression of CD8α |
title_full_unstemmed | Enhancing Efficacy of TCR-engineered CD4(+) T Cells Via Coexpression of CD8α |
title_short | Enhancing Efficacy of TCR-engineered CD4(+) T Cells Via Coexpression of CD8α |
title_sort | enhancing efficacy of tcr-engineered cd4(+) t cells via coexpression of cd8α |
topic | Basic Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10072215/ https://www.ncbi.nlm.nih.gov/pubmed/36826388 http://dx.doi.org/10.1097/CJI.0000000000000456 |
work_keys_str_mv | AT andersonvictoriae enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT brilhasaras enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT weberanikam enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT pachnioannette enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT wiedermannguye enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT daulehsumaya enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT ahmedtina enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT popegeorger enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT quinnlaural enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT doctarosliny enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT quattriniadriano enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT masterssiobhan enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT cartwrightneil enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT viswanathanpreetha enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT melchioriluca enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT ricelouisev enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT sevkoalexandra enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT gueguenclaire enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT sainimanoj enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT tavanobarbara enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT abbottracheljm enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT silkjonathand enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT laugelbruno enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT sandersonjosephp enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a AT gerryandrewb enhancingefficacyoftcrengineeredcd4tcellsviacoexpressionofcd8a |