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TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells
Chimeric antigen receptor (CAR) T cell therapy is used in treating human hematological malignancies, but its efficacy is limited by T cell exhaustion (T(EX)). T(EX) arises at the expense of central memory T cells (T(CM)), which exhibit robust antitumor efficacy. Reduction of the TET2 gene led to inc...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355826/ https://www.ncbi.nlm.nih.gov/pubmed/37467321 http://dx.doi.org/10.1126/sciadv.adh2605 |
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author | Collins, Sierra M. Alexander, Katherine A. Lundh, Stefan Dimitri, Alexander J. Zhang, Zhen Good, Charly R. Fraietta, Joseph A. Berger, Shelley L. |
author_facet | Collins, Sierra M. Alexander, Katherine A. Lundh, Stefan Dimitri, Alexander J. Zhang, Zhen Good, Charly R. Fraietta, Joseph A. Berger, Shelley L. |
author_sort | Collins, Sierra M. |
collection | PubMed |
description | Chimeric antigen receptor (CAR) T cell therapy is used in treating human hematological malignancies, but its efficacy is limited by T cell exhaustion (T(EX)). T(EX) arises at the expense of central memory T cells (T(CM)), which exhibit robust antitumor efficacy. Reduction of the TET2 gene led to increased T(CM) differentiation in a patient with leukemia who experienced a complete remission. We show that loss of TET2 led to increased chromatin accessibility at exhaustion regulators TOX and TOX2, plus increased expression of TOX2. Knockdown of TOX increased the percentage of T(CM). However, unexpectedly, knockdown of TOX2 decreased T(CM) percentage and reduced proliferation. Consistently, a T(CM) gene signature was reduced in the TOX2 knockdown, and TOX2 bound to promoters of numerous T(CM) genes. Our results thus suggest a role for human TOX2, in contrast to exhaustion regulator TOX, as a potentiator of central memory differentiation of CAR T cells, with plausible utility in CAR T cell cancer therapy via modulated TOX2 expression. |
format | Online Article Text |
id | pubmed-10355826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-103558262023-07-20 TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells Collins, Sierra M. Alexander, Katherine A. Lundh, Stefan Dimitri, Alexander J. Zhang, Zhen Good, Charly R. Fraietta, Joseph A. Berger, Shelley L. Sci Adv Biomedicine and Life Sciences Chimeric antigen receptor (CAR) T cell therapy is used in treating human hematological malignancies, but its efficacy is limited by T cell exhaustion (T(EX)). T(EX) arises at the expense of central memory T cells (T(CM)), which exhibit robust antitumor efficacy. Reduction of the TET2 gene led to increased T(CM) differentiation in a patient with leukemia who experienced a complete remission. We show that loss of TET2 led to increased chromatin accessibility at exhaustion regulators TOX and TOX2, plus increased expression of TOX2. Knockdown of TOX increased the percentage of T(CM). However, unexpectedly, knockdown of TOX2 decreased T(CM) percentage and reduced proliferation. Consistently, a T(CM) gene signature was reduced in the TOX2 knockdown, and TOX2 bound to promoters of numerous T(CM) genes. Our results thus suggest a role for human TOX2, in contrast to exhaustion regulator TOX, as a potentiator of central memory differentiation of CAR T cells, with plausible utility in CAR T cell cancer therapy via modulated TOX2 expression. American Association for the Advancement of Science 2023-07-19 /pmc/articles/PMC10355826/ /pubmed/37467321 http://dx.doi.org/10.1126/sciadv.adh2605 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Collins, Sierra M. Alexander, Katherine A. Lundh, Stefan Dimitri, Alexander J. Zhang, Zhen Good, Charly R. Fraietta, Joseph A. Berger, Shelley L. TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells |
title | TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells |
title_full | TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells |
title_fullStr | TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells |
title_full_unstemmed | TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells |
title_short | TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells |
title_sort | tox2 coordinates with tet2 to positively regulate central memory differentiation in human car t cells |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355826/ https://www.ncbi.nlm.nih.gov/pubmed/37467321 http://dx.doi.org/10.1126/sciadv.adh2605 |
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