Sequential 5-aza-2 '-deoxycytidine-depsipeptide FR901228 treatment inducesapoptosis preferentially in cancer cells and facilitates their recognitionby cytolytic T lymphocytes specific for NY-ESO-1

Global alterations in chromatin structure profoundly influence gene express ion in thoracic neoplasms, silencing tumor suppressors while facilitating t he expression of various cancer testis antigens such as NY-ESO-I. Although recent studies have shown that histone deacetylase inhibitors can potentiat e tumor suppressor gene induction mediated by demethylating agents in cance r cells, the ability of these agents to augment cancer testis antigen expre ssion have not been fully defined. The authors designed the current study t o determine whether the histone deacetylase inhibitor, depsipeptide FR90122 8 (DP), could enhance NY-ESO-I induction mediated by the DNA demethylating agent 5-Aza-2'-deoxycytidine (DAC) in cell lines established primarily from thoracic cancers. Quantitative reverse-transcriptase polymerase chain reac tion analysis revealed that, under exposure conditions potentially achievab le in clinical settings, DAC dramatically induced NY-ESO-I expression in cu ltured cancer lines. DP alone mediated negligible target gene induction but significantly augmented DAC-mediated induction of NY-ESO-1. After DAC or s equential DAC-DP treatment, HLA-A*0201 cancer cells were recognized by an H LA-A*0201 CTL specific for NY-ESO-I. Although sequential DAC/DP exposure di d not uniformly enhance immune recognition of target cells compared with DA C alone, this treatment mediated profound induction of apoptosis in cancer cells but not normal human bronchial epithelia. The apoptotic effects of DA C, BP, or sequential DAC-DP did not correlate in an obvious manner with his tology, or the magnitude of NY-ESO-1 induction in cancer cells. Although th e mechanisms have not been fully defined, sequential DAC-DP treatment may b e a novel strategy to augment antitumor immunity in cancer patients.