Chronic viral mimicry induction following p53 loss promotes immune evasion.
Ishak CA., Marhon SA., Tchrakian N., Hodgson A., Loo Yau H., Gonzaga IM., Peralta M., Lungu IM., Gomez S., Liang S-B., Shen SY., Chen R., Chen J., Chatterjee B., Wanniarachchi KN., Lee J., Zehrbach N., Hosseini A., Mehdipour P., Sun S., Solovyov A., Ettayebi I., Francis KE., He A., Wu T., Feng S., da Silva Medina T., Campos de Almeida F., Bayani J., Li J., MacDonald S., Wang Y., Garcia SS., Arthofer E., Diab N., Srivastava A., Austin PT., Sabatini PJB., Greenbaum BD., O'Brien CA., Shepherd TG., Tsao MS., Chiappinelli KB., Oza AM., Clarke BA., Rottapel R., Lheureux S., De Carvalho DD.
Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through 'viral mimicry' responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation that increases cellular tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity. This selection process can be partially attenuated pharmacologically. Altogether, these results reveal that viral mimicry conditioning following p53 loss promotes immune evasion and may represent a pharmacological target for early cancer interception.