Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Cell
Katherine B ChiappinelliReiner Strick

Abstract

We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.

Associated Clinical Trials

References

Mar 22, 1996·Science·D R LeachJ P Allison
Apr 1, 1996·Nature Genetics·T H Bestor, B Tycko
Sep 3, 1996·Proceedings of the National Academy of Sciences of the United States of America·J G HermanS B Baylin
Jun 15, 1997·Nucleic Acids Research·Z Xiong, P W Laird
Nov 26, 1999·Proceedings of the National Academy of Sciences of the United States of America·A R KarpfD A Jones
Oct 10, 2001·Current Biology : CB·G TurnerJ Lenz
Mar 12, 2003·Oncogene·Feng Wang-JohanningGary L Johanning
Mar 22, 2003·RNA·Sheila A StewartCarl D Novina
Aug 18, 2004·Proceedings of the National Academy of Sciences of the United States of America·Norbert Bannert, Reinhard Kurth
Aug 18, 2004·Proceedings of the National Academy of Sciences of the United States of America·Michael F EganDaniel R Weinberger
Sep 10, 2004·Nucleic Acids Research·Jianjun ChenJanet D Rowley
Oct 13, 2004·Retrovirology·Palle VillesenFinn Skou Pedersen
Feb 26, 2005·Journal of Virology·Michael D RobekFrancis V Chisari
May 3, 2005·Nature Reviews. Immunology·Leonidas C Platanias
May 18, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Edvardas KaminskasUNKNOWN FDA
Jan 24, 2006·Experimental Cell Research·Magda MatouskováJirí Hejnar
Mar 3, 2006·Cancer Research·Carlo StresemannFrank Lyko
May 30, 2006·Advances in Immunology·Charles G DrakeDrew M Pardoll
Oct 3, 2006·International Journal of Cancer. Journal International Du Cancer·Feng Wang-JohanningGary L Johanning
Oct 27, 2006·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Reiner StrickPamela L Strissel
May 17, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Raanan BergerArnon Nagler
Sep 27, 2008·Cellular and Molecular Life Sciences : CMLS·I A MaksakovaD Reiss
Mar 31, 2009·Cancer Letters·Julie Mou LarsenLars-Inge Larsson
Oct 8, 2009·Cancer Research·Matthias SchaeferFrank Lyko
Jan 23, 2010·Genes, Chromosomes & Cancer·Sven StengelJoachim Denner
Apr 30, 2010·Bioinformatics·Matthew D Wilkerson, D Neil Hayes
Jun 3, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Julie R BrahmerSuzanne L Topalian
Jun 8, 2010·The New England Journal of Medicine·F Stephen HodiWalter J Urba
Sep 24, 2011·Nature Reviews. Cancer·Stephen B Baylin, Peter A Jones
Jan 17, 2012·Journal of the National Cancer Institute·Feng Wang-JohanningGary L Johanning
Jan 19, 2012·Molecular Cancer Research : MCR·Katherine B ChiappinelliPaul J Goodfellow
Mar 23, 2012·Nature Reviews. Cancer·Drew M Pardoll

❮ Previous
Next ❯

Citations

Feb 18, 2016·The New England Journal of Medicine·Anthony E Dear
Jan 16, 2016·Annual Review of Medicine·Nita AhujaStephen B Baylin
Dec 23, 2015·Wiley Interdisciplinary Reviews. RNA·Brian J LiddicoatCarl R Walkley
Dec 19, 2015·Cancer Cell·Lorenzo GalluzziGuido Kroemer
Dec 10, 2015·Nature Medicine·Randy LevinsonBrett Benedetti
May 4, 2016·Oncoimmunology·David RouloisDaniel D De Carvalho
Mar 22, 2016·Seminars in Immunology·Reno DebetsGeorge Coukos
Mar 26, 2016·Pharmacology & Therapeutics·Mansi A ParasramkaTushar Patel
Mar 31, 2016·Nature Reviews. Immunology·George Kassiotis, Jonathan P Stoye
Aug 12, 2016·Mobile Genetic Elements·Irene Munk Pedersen, Dimitrios G Zisoulis
Apr 18, 2016·Biochimica Et Biophysica Acta·Anna KazanetsMichael Witcher
Apr 16, 2016·Nature Reviews. Cancer·Suzanne L TopalianDrew M Pardoll
Apr 30, 2016·Current Opinion in Microbiology·Nicholas F Parrish, Keizo Tomonaga
Apr 24, 2016·Trends in Immunology·Lauryn E Klevorn, Ryan M Teague
May 14, 2016·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Arnold J LevineBenjamin D Greenbaum
May 21, 2016·Immunotherapy·Manuela Terranova-BarberioPamela N Munster
Jun 20, 2016·Current Opinion in Chemical Biology·Matthieu Schapira, Cheryl H Arrowsmith
Jun 23, 2016·Clinical Epigenetics·Jeannine DieschKatharina S Götze
Jun 28, 2016·Nature Reviews. Genetics·C David Allis, Thomas Jenuwein
Jun 18, 2016·International Journal of Molecular Sciences·Andreas GlenthøjKirsten Grønbæk
Oct 21, 2016·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Cheng-Jun SuiJia-Mei Yang
Oct 8, 2016·Transcription·Didier Auboeuf
Jul 31, 2016·Experimental Hematology·Lu Zhao, Chi Wai Eric So
Aug 31, 2016·Proceedings of the National Academy of Sciences of the United States of America·Minmin LiuPeter A Jones
Nov 26, 2015·Trends in Immunology·Andy J Minn
Sep 16, 2016·Nature Reviews. Genetics·Peter A JonesStephen Baylin
Oct 11, 2016·Mechanisms of Ageing and Development·Clara Soria-VallesCarlos López-Otín
Nov 15, 2016·Nature Medicine·Marta ChesiP Leif Bergsagel
Sep 14, 2016·The Journal of Investigative Dermatology·Valeria LucariniFabrizio Mattei
Mar 11, 2017·Nature Reviews. Drug Discovery·Sophia Xiao Pfister, Alan Ashworth
Jan 19, 2017·Cancer Science·Susumu Goyama, Toshio Kitamura
Feb 6, 2017·Cold Spring Harbor Perspectives in Medicine·Takahiro SatoPatricia Kropf

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Cancer Immunotherapy

Cancer immunotherapy is an important field of research that is looking at controlling cancer and tumor growth by activating the individuals own immune system. Recent studies have utilized chimeric antigen receptor t-cell therapy, immune checkpoint inhibitors and neoantigen vaccines. Discover the latest research on cancer immunotherapy here.

Cell eTOC

Cell is a scientific journal publishing research across a broad range of disciplines within the life sciences field. Discover the latest research from Cell here.

Antigenic Modulation

Antigenic modulation occurs when an antibody cross-links antigens on a cell surface, causing the antigens to become internalized. This can lead to therapeutic failure of monoclonal antibodies as the expression of the antigen becomes decreased on target cells. Find the latest research on antigenic modulation here.

Cancer Epigenetics and Senescence (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may be involved in regulating senescence in cancer cells. This feed captures the latest research on cancer epigenetics and senescence.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Cancer Epigenetics & Metabolism (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may or may not provide advantages for the cancer cells. This feed focuses on the relationship between cell metabolism, epigenetics and tumor differentiation.