Abstract
BackgroundNumerous immune genes are epigenetically silenced in tumor cells and agents such as histone deacetylase inhibitors (HDACi), which reverse these effects, could potentially be used to develop therapeutic vaccines. The conversion of cancer cells to antigen presenting cells (APCs) by HDACi treatment could potentially provide an additional pathway, together with cross-presentation of tumor antigens by host APCs, to establish tumor immunity.MethodsHDACi-treated B16 melanoma cells were used in a murine vaccine model, lymphocyte subset depletion, ELISpot and Cytotoxicity assays were employed to evaluate immunity. Antigen presentation assays, vaccination with isolated apoptotic preparations and tumorigenesis in MHC-deficient mice and radiation chimeras were performed to elucidate the mechanisms of vaccine-induced immunity.ResultsHDACi treatment enhanced the expression of MHC class II, CD40 and B7-1/2 on B16 cells and vaccination with HDACi-treated melanoma cells elicited tumor specific immunity in both prevention and treatment models. Cytotoxic and IFN-γ-producing cells were identified in splenocytes and CD4+, CD8+ T cells and NK cells were all involved in the induction of immunity. Apoptotic cells derived from HDACi treatments, but not H2O2, significantly enhanced the effectiveness of the vaccine. HDACi-treated B16 cells become APCs in vitro and studies in chimeras defective in cross presentation demonstrate direct presentation in vivo and short-term but not memory responses and long-term immunity.ConclusionThe efficacy of this vaccine derives mainly from cross-presentation which is enhanced by HDACi-induced apoptosis. Additionally, epigenetic activation of immune genes may contribute to direct antigen presentation by tumor cells. Epigenetically altered cancer cells should be further explored as a vaccine strategy.
Highlights
Numerous immune genes are epigenetically silenced in tumor cells and agents such as histone deacetylase inhibitors (HDACi), which reverse these effects, could potentially be used to develop therapeutic vaccines
To determine the cell surface expression of MHC class I, class II, CD40, CD80 and CD86 in relation to apoptosis induction, trichostatin A (TSA)-treated (50 nM-1 μM, 12–48 h) adherent (~95% viable) B16 cells were analyzed by flow cytometry
TSA-treated B16 cells retained enhanced expression of these genes over 24 h after withdrawal of treatment in vitro. These results demonstrate that TSA treatment induces apoptosis and elicits expression of class II and costimulatory molecules on B16 tumor cells similar to the results previously reported on the J558 plasmacytoma [4]
Summary
Numerous immune genes are epigenetically silenced in tumor cells and agents such as histone deacetylase inhibitors (HDACi), which reverse these effects, could potentially be used to develop therapeutic vaccines. In some mouse models and the vast majority of human cancers, the tumor vaccines currently employed have not been successful This may be attributed to a failure of adequate stimulation of appropriate components of immunity and/or tolerance to (page number not for citation purposes). Tumor vaccination strategies have focused on enhancing a cytotoxic T cell (CTL) response Activation of both T-helper cells and CTLs is achieved primarily through cross-presentation of tumor antigens by professional antigen presenting cells (APCs) [2]. Cross-presentation is the major mechanism generating immunity [2,3], the above studies on tumors as APC suggest that, at least in certain tumors, direct antigen presentation could provide an alternative or additional pathway in tumor immunity. An important issue is whether direct presentation can be enhanced in vivo and become a quantitatively significant component of tumor immunity
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