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Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy
Histone deacetylase inhibitors (HDACi) are currently being explored for the treatment of both solid and hematological malignancies. Although originally thought to exert cytotoxic responses through tumor-intrinsic mechanisms by increasing expression of tumor suppressor genes, several studies have dem...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513502/ https://www.ncbi.nlm.nih.gov/pubmed/37744352 http://dx.doi.org/10.3389/fimmu.2023.1260545 |
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author | Holay, Nisha Somma, Alexander Duchow, Mark Soleimani, Milad Capasso, Anna Kottapalli, Srividya Rios, Joshua Giri, Uma Diamond, Jennifer Schreiber, Anna Piscopio, Anthony D. Van Den Berg, Carla Eckhardt, S. Gail Triplett, Todd A. |
author_facet | Holay, Nisha Somma, Alexander Duchow, Mark Soleimani, Milad Capasso, Anna Kottapalli, Srividya Rios, Joshua Giri, Uma Diamond, Jennifer Schreiber, Anna Piscopio, Anthony D. Van Den Berg, Carla Eckhardt, S. Gail Triplett, Todd A. |
author_sort | Holay, Nisha |
collection | PubMed |
description | Histone deacetylase inhibitors (HDACi) are currently being explored for the treatment of both solid and hematological malignancies. Although originally thought to exert cytotoxic responses through tumor-intrinsic mechanisms by increasing expression of tumor suppressor genes, several studies have demonstrated that therapeutic responses depend on an intact adaptive immune system: particularly CD8 T cells. It is therefore critical to understand how HDACi directly affects T cells in order to rationally design regimens for combining with immunotherapy. In this study, we evaluated T cell responses to a novel class-selective HDACi (OKI-179, bocodepsin) by assessing histone acetylation levels, which revealed rapid responsiveness accompanied by an increase in CD4 and CD8 T cell frequencies in the blood. However, these rapid responses were transient, as histone acetylation and frequencies waned within 24 hours. This contrasts with in vitro models where high acetylation was sustained and continuous exposure to HDACi suppressed cytokine production. In vivo comparisons demonstrated that stopping OKI-179 treatment during PD-1 blockade was superior to continuous treatment. These findings provide novel insight into the direct effects of HDAC inhibitors on T cells and that treatment schedules that take into account acute T cell effects should be considered when combined with immunotherapies in order to fully harness the tumor-specific T cell responses in patients. |
format | Online Article Text |
id | pubmed-10513502 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-105135022023-09-22 Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy Holay, Nisha Somma, Alexander Duchow, Mark Soleimani, Milad Capasso, Anna Kottapalli, Srividya Rios, Joshua Giri, Uma Diamond, Jennifer Schreiber, Anna Piscopio, Anthony D. Van Den Berg, Carla Eckhardt, S. Gail Triplett, Todd A. Front Immunol Immunology Histone deacetylase inhibitors (HDACi) are currently being explored for the treatment of both solid and hematological malignancies. Although originally thought to exert cytotoxic responses through tumor-intrinsic mechanisms by increasing expression of tumor suppressor genes, several studies have demonstrated that therapeutic responses depend on an intact adaptive immune system: particularly CD8 T cells. It is therefore critical to understand how HDACi directly affects T cells in order to rationally design regimens for combining with immunotherapy. In this study, we evaluated T cell responses to a novel class-selective HDACi (OKI-179, bocodepsin) by assessing histone acetylation levels, which revealed rapid responsiveness accompanied by an increase in CD4 and CD8 T cell frequencies in the blood. However, these rapid responses were transient, as histone acetylation and frequencies waned within 24 hours. This contrasts with in vitro models where high acetylation was sustained and continuous exposure to HDACi suppressed cytokine production. In vivo comparisons demonstrated that stopping OKI-179 treatment during PD-1 blockade was superior to continuous treatment. These findings provide novel insight into the direct effects of HDAC inhibitors on T cells and that treatment schedules that take into account acute T cell effects should be considered when combined with immunotherapies in order to fully harness the tumor-specific T cell responses in patients. Frontiers Media S.A. 2023-09-06 /pmc/articles/PMC10513502/ /pubmed/37744352 http://dx.doi.org/10.3389/fimmu.2023.1260545 Text en Copyright © 2023 Holay, Somma, Duchow, Soleimani, Capasso, Kottapalli, Rios, Giri, Diamond, Schreiber, Piscopio, Van Den Berg, Eckhardt and Triplett 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 Holay, Nisha Somma, Alexander Duchow, Mark Soleimani, Milad Capasso, Anna Kottapalli, Srividya Rios, Joshua Giri, Uma Diamond, Jennifer Schreiber, Anna Piscopio, Anthony D. Van Den Berg, Carla Eckhardt, S. Gail Triplett, Todd A. Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy |
title | Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy |
title_full | Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy |
title_fullStr | Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy |
title_full_unstemmed | Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy |
title_short | Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy |
title_sort | elucidating the direct effects of the novel hdac inhibitor bocodepsin (oki-179) on t cells to rationally design regimens for combining with immunotherapy |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513502/ https://www.ncbi.nlm.nih.gov/pubmed/37744352 http://dx.doi.org/10.3389/fimmu.2023.1260545 |
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