An Intact Immune System Is Required for the Anticancer Activities of Histone Deacetylase Inhibitors

Abstract

Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major antitumor responses to histone deacetylase inhibitors (HDACi). These compounds can also mediate immune-modulatory effects that may contribute to their anticancer 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 physiologic setting, using preclinical, syngeneic murine models of hematologic malignancies and solid tumors. We showed an intact immune system was required for the robust anticancer effects of the HDACi vorinostat and panobinostat against a colon adenocarcinoma and two aggressive models of leukemia/lymphoma. Importantly, although HDACi-treated immunocompromised mice bearing established lymphoma succumbed to disease significantly earlier than tumor bearing, HDACitreated wild-type (WT) mice, treatment with the conventional chemotherapeutic etoposide equivalently enhanced the survival of both strains. IFN-g and tumor cell signaling through IFN-gR were particularly important for the anticancer effects of HDACi, and vorinostat and IFN-g acted in concert to enhance the immunogenicity of tumor cells. Furthermore, we show that a combination of vorinostat with a-galactosylceramide (a-GalCer), an IFN-g-inducing agent, was significantly more potent against established lymphoma than vorinostat treatment alone. Intriguingly, B cells, but not natural killer cells or CD8 þ T cells, were implicated as effectors of the vorinostat antitumor immune response. Together, our data suggest HDACi are immunostimulatory during cancer treatment and that combinatorial therapeutic regimes with immunotherapies should be considered in the clinic. Cancer Res; 73(24); 7265-76. Ó2013 AACR.

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

“…40 This was felt to be important, due to the observation that histone deacetylase (HDAC) inhibition may have immunoregulatory effects in other malignancies, such as Hodgkin's lymphoma and myeloma, and their efficacy requires an intact immune system. [41][42][43] HDAC inhibition may therefore be particularly effective in malignancies that are poorly immunogenic and in tumors that are associated with an immunosuppressive microenvironment, such as malignant glioma. 44 Even though this effect of HDAC inhibition has yet to be demonstrated in HGG, we did not want to negate any potential immunotherapeutic effect of panobinostat delivered by CED by using an immunocompromised rat-human glioma xenograft.…”

Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

“…These groups are based on their ability to trigger both cancer cell death as well as danger signaling as a consequence of direct induction of ER-stress (Type II inducers), or whether the inducer evokes ER stress-based danger signaling and apoptosis/cell death through convergent, but mechanistically separate targets (Type I inducers). 33,38 Type I inducers of ICD such as anthracyclines, 4,39 oxaliplatin, 40 shikonin, 41 7A7 (murine EGFR-specific antibody), 42 cyclophosphamide, 43 bortezomib, 27 cardiac glycosides, 44 septacidin, 45 bleomycin, 46 ultraviolet C light (UVC), 14 wogonin, 47 vorinostat, 48 g-irradiation 14 and newly described HHP 49,50 target mainly cytosolic proteins, plasma membrane channels or proteins, or DNA replication and repair machinery, rather than primarily targeting the ER. 33 On the other hand, Type II inducers which specifically target the ER include PDT with Hypericin (Hyp-PDT), 51 and various different oncolytic viruses.…”

Manipulation of B-cell responses with histone deacetylase inhibitors

“…The wealth of experimental data on the effect of HDACi on cancer cells including haematological malignancies, has progressed these compounds into the clinic. Interestingly, emerging data illustrate that HDACi can also modify lymphocyte subsets such as T cells 21,22 , T regs 23 and B cells 24,25 . The potential to modify autoantibody responses is highlighted by data illustrating experimental HDACi such as Trichostatin A (which has not progressed into the clinic) can reduce antibody production in cell lines in vitro 24 while vorinostat treatment of MRL/lpr mice dampens immune cytokines such as IL-2, IFN-g, IL-6 and IL-10 (ref.…”