Tumor vaccination with epigenetically altered tumor cells

Presentation of tumor antigens by antigen presenting cells (APCs) can induce immunity against malignant cells. The conversion of cancer cells to effective APCs could potentially provide an alternative or additional pathway to establish tumor immunity. Histone deacetylase inhibitors, such as Trichostatin A (TSA), can enhance immune gene transcription in tumor cells by altering the acetylation status of chromatin. TSA treatment also elicits apoptosis in tumor cells. This study was constructed to determine whether TSA treatment can convert tumor cells to APCs and whether those altered tumor cells could be used as a vaccine in a murine tumor model. We show that the expression of MHC class II, CD40 and B7-1/2 molecules are enhanced in J558 plasmacytoma and B16 melanoma cells after treatment with TSA. Tumor cells treated in vitro with TSA, when inoculated in syngeneic mice, elicited immunity in approximately 30% of the plasmacytoma and more than 60% of the melanoma injected animals. Long-term tumor specific immunity to re-challenge with untreated cells was observed in all of these immune animals. IFN-gamma producing cells and T cells with tumor specific cytolytic activity were isolated from immune mice. CD4+ and CD8+ T cells were involved in induction of immunity. Although NK cells alone were not sufficient to generate immunity, the presence of NK cells appears to be required in activation of immunity. TSA treated, but not untreated, tumor cells were capable of presenting protein and peptide antigens to stimulate T cells in vitro. In the absence of cross-presentation TSA treated tumor cells delayed tumor generation suggesting that direct antigen presentation by altered tumor cells was a component in immunity generation in vivo. TSA treated, but not H2O2 treated, apoptotic tumor cells induced durable immunity suggesting a selective role for the TSA treated apoptotic cells in induction of immunity. We conclude that reversal of gene silencing by treatment with a histone deacetylase inhibitor can generate an effective cell-based tumor vaccine. This study suggests that repression of immune genes is involved in the evasion of immunity by tumors and epigenetically altered cancer cells should be further explored as a strategy for the induction of tumor immunity.