Scientists from UHN’s Princess Margaret Cancer Centre (PM) have found that certain repetitive elements in DNA contribute to cancer initiation by evading immune defences.
The human genome contains repetitive DNA elements that are mostly kept silent, meaning they do not make any molecules such as proteins or RNA. Some emerging cancer therapies work by reversing this silencing, allowing the elements to be expressed. Previous research by Dr. Daniel D. De Carvalho, Senior Scientist at PM, has shown that this anti-cancer effect is due to a process called ‘viral mimicry,’ where cancer cells behave as if they are infected by a virus. This triggers an immune response that can kill cancer cells.
However, research has also found that the transcription of repetitive DNA elements is associated with cancer initiation. If expressing these elements can kill cancer cells, why do most human cancers express them?
To investigate this paradox, Dr. De Carvalho’s team studied how these repetitive DNA elements relate to cancer initiation. They examined the earliest stages of tumour development following the loss of the TP53 gene in fallopian tube tissues and ovarian cancer models. TP53 is a tumour suppressor gene that regulates cell division and cell death and is frequently mutated in many cancers.
The silencing of tumour suppressor genes—which normally keep cell division and growth in check—has been linked to the activation of repetitive DNA elements. Since TP53 is the most frequently mutated tumour suppressor in human cancers, the team focused their research on the events that follow mutations in this gene.
By analyzing genes and their activity in precancerous tissue, the researchers found that these cells had abnormal activation of repetitive genetic elements. In laboratory models, disabling TP53 led to the expression of these elements, which then triggered a chronic viral mimicry response.
The team then discovered that this immune activation forces cancer cells to adapt, reducing immune responses and helping cancer evade the immune system and resist certain therapies. The researchers named this process ‘viral mimicry conditioning’.
“Our results show that in malignant transformation, cells chronically exposed to a viral mimicry response become tolerant to immune activation. This leads to cancers, such as ovarian cancers, that do not respond to immunotherapy,” says Dr. De Carvalho, senior author of the study. “Targeting this process of viral mimicry conditioning could offer new ways to stop cancer early by enabling immune surveillance.”
To explore potential treatments, the team tested an FDA-approved drug called lamivudine. They found that it could partially block viral mimicry conditioning, suggesting a new treatment and interception strategy for these types of cancers.
This study enhances our understanding of how repetitive DNA elements and immune activation contribute to early cancer development. These findings could lead to more effective treatment and interception strategies.
Dr. Charles A. Ishak is co-first author of this study. He is a former postdoctoral researcher at UHN and is currently an Assistant Professor at MD Anderson Cancer Center.
Dr. Sajid A. Marhon is co-first author of this study and a Scientific Associate at UHN.
Dr. Daniel D. De Carvalho is a Senior Scientist at Princess Margaret Cancer Centre and senior author of the study. He is also a Professor in the Department of Medical Biophysics at the University of Toronto.
This work was supported by the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, the William Guy Forbeck Research Foundation, the National Cancer Institute, the National Institutes of Health, Marlene and Michael Berman Endowed Fund for Ovarian Cancer Research, and The Princess Margaret Cancer Foundation.
Dr. Carvalho is a Tier 2 Canada Research Chair in Cancer Epigenetics and Epigenetic Therapy.
Ishak CA, Marhon SA, Tchrakian N, Hodgson A, Loo Yau H, Gonzaga IM, Peralta M, Lungu IM, Gomez S, Liang SB, 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. Chronic viral mimicry induction following p53 loss promotes immune evasion. Cancer Discov. 2025 Jan 7. doi: 10.1158/2159-8290.CD-24-0094. Epub ahead of print.