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Developmental Biology - Immune Response
Activating Our Own Immune System Against Cancer
Ancient elements embedded in our DNA for generations can activate a powerful immune response, killing cancer cells as if an infection...
The work builds on Princess Margaret Senior Scientist Daniel De Carvalho's previous ground-breaking discovery known as - the ability to cause cancer cells to behave as though they have been infected, thus activating the immune system to fight cancer like an infection.
Daniel De Carvalho PhD and his team have now identified silent ancient DNA elements buried in our genome that when 'reactivated' can initiate this immune response. Importantly, they have also discovered a key enzyme used by cancer cells to prevent this from happening in order to survive.
The enzyme is known as ADAR1, and it acts to prevent cancer cells from signalling the immune system. Dr. De Carvalho, Associate Professor, Medical Biophysics, University of Toronto, discovered that by inhibiting this enzyme, cancer cells were more sensitive to new drug therapies that induce viral mimicry.
The research published online on October 21, 2020 in Nature, under the title, "Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency." First authors on the study are Parinaz Mehdipour PhD, Sajid Marhon PhD and Masters' graduate student Ilias Ettayebi, trainees in Dr. De Carvalho's laboratory.
"Humans acquired a series of 'silent' repetitive elements in our DNA over millions of years of evolution, but it has been unclear why or what purpose they serve. As 'genome archeologists', we set out to identify the function of these 'DNA relics' and have found that under the right conditions they can be reactivated to stimulate our immune system."
Daniel D. De Carvalho PhD, Princess Margaret Cancer Centre, University Health Network, and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
De Carvalho's discovery of the ADAR1 enzyme explains how some cancer cells mount a defense against this process, protecting themselves from our immune system.
"These findings open up a new field of cancer therapies," explains De Carvalho. "giving us the opportunity to take advantage of these ancient repetitive DNA elements to fight cancer."
Studying the potential to modulate the immune response against tumour cells is one of the most rapidly changing and exciting areas in clinical oncology.
While much knowledge has been gained about how the immune system interacts with cancer, leading to the development of novel immunotherapy drugs, a large proportion of cancer patients do not respond to immunotherapy alone.
In De Carvalho's initial discovery, epigenetic drugs were shown to reactivate these ancient repetitive DNA elements and led to the production of double-stranded RNA, a molecular pattern also observed following viral infection.
This 'viral mimicry' leads to an antiviral response directed specifically against cancer cells. In this latest research, De Carvalho's lab identified the specific ancient repetitive DNA elements as SINEs (Short Interspersed Nuclear Elements). These SINEs usually lie quiet in our genome, having little effect on the host - us.
However, if activated by new epigenetic drugs, these SINES produce double-stranded RNA - a marker for infection - and can ultimately be used by cells to trigger an innate immune response.
Dr. De Carvalho likens this response "to an ancient dagger that can be used against cancer."
But cancer cells are wily and have also evolved to evade detection by the immune system even under conditions where the ancient DNA sequences are activated.
Dr. De Carvalho discovered that cancer cells strike back by making more of the ADAR1 enzyme, which functions to disrupts the double-stranded RNA produced by the ancient DNA. In this way ADAR1 prevents the cancer cells from activating the immune system.
Dr. Carvalho and his team went on to demonstrate that deleting ADAR1 from cancer cells makes them exquisitely vulnerable to epigenetic drugs that induce the antiviral response.
"As ADAR1 activity is enzymatic, our work provides an exciting new target for drug development efforts for a completely new class of drugs that are able to exploit these 'ancient weapons' in our genome."
Daniel D. De Carvalho PhD
Abstract
Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor1,2,3,4,5,6. This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses7,8. However, the clinical efficacy of epigenetic therapies has been limited. To find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. Here we show that intronic and intergenic SINE elements, specifically inverted-repeat Alus, are the major source of drug-induced immunogenic dsRNA. These inverted-repeat Alus are frequently located downstream of ‘orphan’ CpG islands9. In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA10, which prevents activation of the MDA5 receptor11. We found that ADAR1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy for cancer treatment.
Authors
Parinaz Mehdipour, Sajid A. Marhon, Ilias Ettayebi, Ankur Chakravarthy, Amir Hosseini, Yadong Wang, Fabíola Attié de Castro, Helen Loo Yau, Charles Ishak, Sagi Abelson, Catherine A. O’Brien and Daniel D. De Carvalho.
Acknowledgements
The authors thank S. Hur and X. Mu for providing the recombinant MDA5 proteins and the protocol for the MDA5-protection assay. We thank the Ontario Institute for Cancer Research (OICR) Genomics for conducting library preparation and RNA-sequencing for the MDA5-protection assay. We also thank the Princess Margaret Cancer Centre Genomics core (PM Genomics) for library preparation and RNA sequencing. This work was funded by Canadian Institute of Health Research (CIHR), New Investigator salary award (201512MSH360794-228629), Helen M Cooke professorship from Princess Margaret Cancer Foundation, Canada Research Chair, CIHR Foundation Grant (FDN 148430), CIHR Project Grant (PJT 165986), NSERC (489073) and Ontario Institute for Cancer Research (OICR) with funds from the province of Ontario to D.D.D.C. P.M. was supported by a Princess Margaret Post-doctoral fellowship- Hold’em for life. I.E. was supported by the Canadian Institutes of Health Research Canada Graduate Scholarships—Masters Award (CGS-M). F.A.d.C. was supported by FAPESP fellowship (2015/21237-4).
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Oct 27 2020 Fetal Timeline Maternal Timeline News
 The ensyme known as ADAR1 acts to prevent cancer cells from signalling the immune system. By inhibiting this ensyme, cancer cells become more sensitive to drug therapies. CREDIT Wikipedia.
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