Chronic viral mimicry induction following p53 loss promotes immune evasion
Charles A. Ishak, Sajid A. Marhon, Nairi Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M. Gonzaga, Melanie Peralta, Ilinca M. Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N. Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E. Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago da Silva Medina, Felipe Campos de Almeida, Jane Bayani, Jason Li, Spencer MacDonald, Yadong Wang, Sarah S. Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran. Austin, Peter J.B. Sabatini, Benjamin D. Greenbaum, Catherine A. O'Brien, Trevor G. Shepherd, Ming Sound Tsao, Katherine B. Chiappinelli, Amit M. Oza, Blaise A. Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D. De CarvalhoAbstract
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.