An intact immune system is required for the anti-cancer activities of histone deacetylase inhibitors
Menée à l'aide de divers modèles murins, cette étude met en évidence des mécanismes par lesquels le système immunitaire module l'efficacité des inhibiteurs d'histone désacétylase tels que le vorinostat et le panobinostat
Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major anti-tumor responses to histone deacetylase inhibitors (HDACi). These compounds can also mediate immune-modulatory effects that may also contribute to their anti-cancer effects. However, HDACi can also induce anti-inflammatory, and potentially immunosuppressive, outcomes. We therefore sought to clarify the role of the immune system in mediating the efficacy of HDACi in a physiological setting, utilising pre-clinical, syngeneic murine models of haematological malignancies and solid tumors. We showed an intact immune system was required for the robust anti-cancer effects of the HDACi vorinostat and panobinostat against a colon adenocarcinoma and two aggressive models of leukemia/lymphoma. Importantly, while HDACi-treated immunocompromised mice bearing established lymphoma succumbed to disease significantly earlier than tumor-bearing, HDACi-treated wild type mice, treatment with the conventional chemotherapeutic etoposide equivalently enhanced the survival of both strains. IFN-γ and tumor cell signaling through IFN-γR were particularly important for the anti-cancer effects of HDACi, and vorinostat and IFN-γ acted in concert to enhance the immunogenicity of tumor cells. Furthermore, we show that a combination of vorinostat with α-GalCer, an IFN-γ-inducing agent, was significantly more potent against established lymphoma than vorinostat treatment alone. Intriguingly, B cells, but not NK cells or CD8+ T cells, were implicated as effectors of the vorinostat anti-tumor immune response. Together our data suggests HDACi are immunostimulatory during cancer treatment and that combinatorial therapeutic regimes with immunotherapies should be considered in the clinic.