The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy.
Cancer Immunol Immunother
; 67(3): 381-392, 2018 03.
Article
em En
| MEDLINE
| ID: mdl-29124315
ABSTRACT
Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells. Mocetinostat upregulated PD-L1 and antigen presentation genes including class I and II human leukocyte antigen (HLA) family members in a panel of NSCLC cell lines in vitro. Mocetinostat target gene promoters were occupied by a class I HDAC and exhibited increased active histone marks after mocetinostat treatment. Mocetinostat synergized with interferon γ (IFN-γ) in regulating class II transactivator (CIITA), a master regulator of class II HLA gene expression. In a syngeneic tumor model, mocetinostat decreased intratumoral T-regulatory cells (Tregs) and potentially myeloid-derived suppressor cell (MDSC) populations and increased intratumoral CD8+ populations. In ex vivo assays, patient-derived, mocetinostat-treated Tregs also showed significant down regulation of FOXP3 and HELIOS. The combination of mocetinostat and a murine PD-L1 antibody antagonist demonstrated increased anti-tumor activity compared to either therapy alone in two syngeneic tumor models. Together, these data provide evidence that mocetinostat modulates immune-related genes in tumor cells as well as immune cell types in the tumor microenvironment and enhances checkpoint inhibitor therapy.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Benzamidas
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Apresentação de Antígeno
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Carcinoma Pulmonar de Células não Pequenas
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Antígeno B7-H1
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Histona Desacetilases
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Neoplasias Pulmonares
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Anticorpos Monoclonais
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article