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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
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.
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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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