Turning T cells on: epigenetically enhanced effector T cell activity following tumor cellirradiation (P2091)

Abstract

Abstract While sub-lethal tumor irradiation enhances killing of colorectal carcinoma cells by tumor-specific CD8+ CTLs, the mechanisms responsible for increased activity of CTLs to irradiated tumor cells remain unknown. Two members of the tumor necrosis family super family of receptors, OX40L/TNFSF4 and 41BBL/TNFSF9, enhance CTL activation and survival. Our results indicate sub-lethal doses of radiation increase tumor cell expression of 41BBL and OX40L via epigenetic mechanisms as inhibition of HDACs (with TSA) and of DNMTs (with 5-AZA) results in significantly increased OX40L and 41BBL mRNA and protein. The combination of radiation and epigenetic modifiers results in greater expression of both receptors, suggesting overlap in the mechanisms by which radiation, 5-AZA, and TSA regulate OX40L and 41BBL. Finally, chromatin immunoprecipitation experiments reveal significantly increased H3 acetylation of 41BBL promoters following irradiation. Our results show non-lethal doses of radiation make human tumors amenable to immune system attack through epigenetic modulation of genes stimulatory to CTLs. The use of ionizing radiation to specifically enhance cancer immunotherapy strategies, through epigenetic modulation of genes stimulatory to CTLs, will have a broad impact on cancer therapy strategies and will extend the use of radiation in new directions.