Chronic viral mimicry induction following p53 loss promotes immune evasion Journal Article
| Authors: | Ishak, C. A.; Marhon, S. A.; Tchrakian, N.; Hodgson, A.; Yau, H. L.; Gonzaga, I. M.; Peralta, M.; Lungu, I. M.; Gomez, S.; Liang, S. B.; Shen, S. Y.; Chen, R.; Chen, J.; Chatterjee, B.; Wanniarachchi, K. N.; Lee, J.; Zehrbach, N.; Hosseini, A.; Mehdipour, P.; Sun, S.; Solovyov, A.; Ettayebi, I.; Francis, K. E.; He, A.; Wu, T.; Feng, S.; da Silva Medina, T.; de Almeida, F. C.; Bayani, J.; Li, J.; MacDonald, S.; Wang, Y.; Garcia, S. S.; Arthofer, E.; Diab, N.; Srivastava, A.; Austin, P. T.; Sabatini, P. J. B.; Greenbaum, B. D.; O’Brien, C. A.; Shepherd, T. G.; Tsao, M. S.; Chiappinelli, K. B.; Oza, A. M.; Clarke, B. A.; Rottapel, R.; Lheureux, S.; De Carvalho, D. D. |
| Article Title: | Chronic viral mimicry induction following p53 loss promotes immune evasion |
| Abstract: | 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 toward cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we character-ize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following the loss of the p53 tumor suppressor protein. We report that p53 loss permits the 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 pharmacologic target for early cancer interception. Significance: Our landmark discovery of viral mimicry characterized repetitive elements as immunogenic stimuli that cull cancer cells. If expressed repetitive elements cull cancer cells, why does every human cancer express repetitive elements? Our report offers an exciting advancement toward understanding this paradox and how to exploit this mechanism for cancer interception. © 2025 American Association for Cancer Research. |
| Keywords: | controlled study; protein expression; gene mutation; genetics; nonhuman; flow cytometry; dna replication; neoplasm; neoplasms; ki 67 antigen; cd8+ t lymphocyte; cell proliferation; animal cell; mouse; animal tissue; cell viability; dna damage; gene expression; cell growth; animal experiment; animal model; small interfering rna; cohort analysis; genotype; body weight; transcription factor; genetic transcription; antineoplastic activity; immunofluorescence; protein p53; carcinogenesis; immunology; immune response; genetic transfection; gamma interferon; cell culture; early cancer; epigenetics; histone methyltransferase; immunogenicity; cancer cell; western blotting; ovary carcinoma; immunoprecipitation; epithelium cell; tumor suppressor protein p53; tumor immunity; cell fractionation; cell count; down regulation; real time polymerase chain reaction; upregulation; immunostimulation; adaptive immunity; cytokine release; homeostasis; analysis of variance; centrifugation; fluorescence activated cell sorting; transcription factor e2f1; immunocompetent cell; cytosol; azacitidine; rna extraction; cyclin dependent kinase 4; heterochromatin; transferrin; cyclin dependent kinase 1; microdissection; nucleic acid; cyclin dependent kinase 2; immune evasion; cyclin a2; retroposon; minichromosome maintenance protein 2; minichromosome maintenance protein 4; minichromosome maintenance protein 6; minichromosome maintenance protein 7; rna isolation; cell cycle protein 20; laser capture microdissection; peritoneal cavity; gene ontology; interferon regulatory factor 7; fallopian tube; molecular mimicry; cyclin b2; chemoluminescence; methyltransferase inhibitor; abdominal circumference; humans; human; male; female; article; rna sequencing; gene set enrichment analysis; crispr-cas9 system; single cell rna seq; id8 cell line; short interspersed nuclear element; interferon induced helicase c domain containing protein 1; biological mimicry; chronic viral mimicry |
| Journal Title: | Cancer Discovery |
| Volume: | 15 |
| Issue: | 4 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-04-01 |
| Start Page: | 793 |
| End Page: | 817 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-24-0094 |
| PUBMED: | 39776167 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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