Class I histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer

Abstract

Objective Patients with epithelial ovarian cancer (EOC) typically present with late‐stage disease, posing a significant challenge to treatment. Although taxane and platinum‐based chemotherapy plus surgical debulking are initially effective, EOC is marked by frequent recurrence with resistant disease. Immunotherapy represents an appealing treatment paradigm given the ability of immune cells to engage metastatic sites and impede recurrence; however, response rates to checkpoint blockade in ovarian cancer have been disappointing. Here, we tested whether class I HDAC inhibition can promote anti‐tumor T cell responses in a spontaneous and nonspontaneous murine model of EOC. Methods We used the spontaneous Tg‐MISIIR‐Tag and nonspontaneous ID8 models of murine ovarian cancer to test this hypothesis. Whole tumor transcriptional changes were assessed using the nCounter PanCancer Mouse Immune Profiling Panel. Changes in select protein expression of regulatory and effector T cells were measured by flow cytometry. Results We found that treatment with the class I HDAC inhibitor entinostat upregulated pathways and genes associated with CD8 T cell cytotoxic function, while downregulating myeloid derived suppressor cell chemoattractants. Suppressive capacity of regulatory T cells within tumors and associated ascites was significantly reduced, reversing the CD8‐Treg ratio. Conclusions Our findings suggest class I HDAC inhibition can promote activation of intratumoral CD8 T cells, potentially by compromising suppressive networks within the EOC tumor microenvironment. In this manner, class I HDAC inhibition might render advanced‐stage EOC susceptible to immunotherapeutic treatment modalities.

Panobinostat enhances olaparib efficacy by modifying expression of homologous recombination repair and immune transcripts in ovarian cancer

“…Moreover, epigenetic drugs such as HDACi are known to have immunomodulatory functions that increase cytotoxic T cell functions 25. , 26. , 27.…”

“…Both PARPi and HDACi are known to alter function of specific immune cell types in the tumor microenvironment to promote anti-tumor immunity 25. , 26. , 27.…”

HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling

“…The activity of class I HDAC inhibitors has been linked to immunomodulatory effects. In particular, MS-275 promotes the activation of intra-tumoral CD8 T cells [ 57 , 58 ]. Our results demonstrate that HDAC1–2 inhibition by MS-275 may directly impact on the plasticity and functions of the MCs monolayer independently of the concomitant effects on EOC cells and on the regulation of the immune system.…”

HDAC1-3 inhibition increases SARS-CoV-2 replication and productive infection in lung mesothelial and epithelial cells

“…The activity of class I HDAC inhibitors has also been linked to immunomodulatory effects. MS-275 has been demonstrated to promote activation of intra-tumoral CD8 T cells ( Hicks et al., 2021 ; McCaw et al., 2021 ). We and others previously demonstrated an antifibrotic role of MS-275 and other class I inhibitors in MCs and other cellular types, which is potentially beneficial in the therapy of lung fibrosis, a frequently reported COVID-19 sequela ( Kim et al., 2018 ; Rossi et al., 2018 ; McGroder et al., 2021 ; Bontempi et al., 2022 ).…”