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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...

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Autores principales: Collins, Sierra M., Alexander, Katherine A., Lundh, Stefan, Dimitri, Alexander J., Zhang, Zhen, Good, Charly R., Fraietta, Joseph A., Berger, Shelley L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
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.
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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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