Chronic viral mimicry induction following p53 loss promotes immune evasion

Charles A. Ishak, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
Sajid A. Marhon, University Health Network, Toronto, Canada.
Nairi Tchrakian, University Health Network, Toronto, Canada.
Anjelica Hodgson, University Health Network, Toronto, ON, Canada.
Helen Loo Yau, University Health Network, Toronto, Canada.
Isabela M. Gonzaga, University Health Network, Toronto, Ontario, Canada.
Melanie Peralta, Mount Sinai Hospital, Toronto, Ontario, Canada.
Ilinca M. Lungu, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Stephanie Gomez, George Washington University, Washington, DC, United States.
Sheng-Ben Liang, University Health Network, Toronto, ON, Canada.
Shu Yi Shen, Adela Canada Inc, Toronto, ON, Canada.
Raymond Chen, University Health Network, Toronto, Ontario, Canada.
Jocelyn Chen, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada, Canada.
Biji Chatterjee, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
Kevin N. Wanniarachchi, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
Junwoo Lee, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
Nicholas Zehrbach, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
Amir Hosseini, University of Oxford, United Kingdom.
Parinaz Mehdipour, University of Oxford, United Kingdom.
Siyu Sun, Memorial Sloan Kettering Cancer Center, United States.
Alexander Solovyov, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Ilias Ettayebi, University of Toronto, Princess Margaret Cancer Center-University Health Network, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Kyle E. Francis, Princess Margaret Cancer Centre, Toronto, ON, Canada.
Aobo He, University of Toronto, Toronto, ON, Canada.
Taiyi Wu, University of Toronto, Toronto, ON, Canada.
Shengrui Feng, Princess Margaret Cancer Centre, Toronto, ON, Canada.
Tiago da Silva Medina, A.C.Camargo Cancer Center, Sao Paulo, Sao Paulo, Brazil.
Felipe Campos de Almeida, Princess Margaret Cancer Centre, Toronto, ON, Canada.
Jane Bayani, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Jason Li, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Spencer MacDonald, Princess Margaret Cancer Centre, Canada.
Yadong Wang, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Document Type

Journal Article

Publication Date

1-7-2025

Journal

Cancer discovery

DOI

10.1158/2159-8290.CD-24-0094

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 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.

Department

Microbiology, Immunology, and Tropical Medicine

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