Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy

Frontiers in Immunology

Immunology

Milad Soleimani¹  S. Gail Eckhardt¹  Nisha Holay¹  Carla Van Den Berg²  Uma Giri³  Srividya Kottapalli³  Joshua Rios³  Anna Capasso³  Alexander Somma³  Mark Duchow³  Todd A. Triplett⁴  Anthony D. Piscopio⁵  Jennifer Diamond⁶  Anna Schreiber⁷ 

[1] Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, TX, United States;Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, United States;Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, TX, United States;Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, United States;Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX, United States;Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, United States;Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, United States;Department of Immunotherapeutics & Biotechnology, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States;OnKure Therapeutics, Boulder, CO, United States;OnKure Therapeutics, Boulder, CO, United States;University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Denver, CO, United States;University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Denver, CO, United States;

关键词: T cell;    colorectal cancer;    HDAC;    HDAC inhibitors;    cancer;    immunotherapy;    immunology;   

DOI  :  10.3389/fimmu.2023.1260545

 received in 2023-07-18, accepted in 2023-08-23,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Holay, Somma, Duchow, Soleimani, Capasso, Kottapalli, Rios, Giri, Diamond, Schreiber, Piscopio, Van Den Berg, Eckhardt and Triplett