Integrity of the Antiviral STING-mediated DNA Sensing in Tumor Cells Is Required to Sustain the Immunotherapeutic Efficacy of Herpes Simplex Oncolytic Virus

Cancers
Guendalina FroechlichNicola Zambrano

Abstract

The dichotomic contribution of cancer cell lysis and tumor immunogenicity is considered essential for effective oncovirotherapy, suggesting that the innate antiviral immune response is a hurdle for efficacy of oncolytic viruses. However, emerging evidence is resizing this view. By sensing cytosolic DNA, the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) axis can both counteract viral spread and contribute to the elicitation of adaptive immunity via type I interferon responses. In this paper, we analyzed the tumor-resident function of Sting-mediated DNA sensing in a combined approach of oncovirotherapy and PD-1 immune checkpoint blockade, in an immunocompetent murine model. While supporting increased lytic potential by oncolytic HER2-retargeted HSV-1 in vitro and in vivo, Sting-knockout tumors showed molecular signatures of an immunosuppressive tumor microenvironment. These signatures were correspondingly associated with ineffectiveness of the combination therapy in a model of established tumors. Results suggest that the impairment in antiviral response of Sting-knockout tumors, while favoring viral replication, is not able to elicit an adequate immunotherapeutic effect, due to lack of immunogenic cell...Continue Reading

References

Mar 30, 2004·Journal of Virology·Ana Virginia Chee, Bernard Roizman
Sep 27, 2013·Journal of Virology·Helen L ZennerColin M Crump
Dec 18, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Samuel T WorkenheKaren L Mossman
Nov 5, 2014·Proceedings of the National Academy of Sciences of the United States of America·Maria KalamvokiBernard Roizman
Mar 21, 2015·BioMed Research International·Emanuele SassoNicola Zambrano
May 13, 2015·Frontiers in Immunology·Lucillia BezuGuido Kroemer
Sep 2, 2015·Nature Reviews. Drug Discovery·Howard L KaufmanAndrew Zloza
Feb 13, 2016·Cell Host & Microbe·Zhe Ma, Blossom Damania
Jan 18, 2017·Proceedings of the National Academy of Sciences of the United States of America·Kenji ChamotoTasuku Honjo
Feb 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Hua WangZhijian J Chen
Oct 6, 2017·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jason ChesneyHoward L Kaufman
Mar 6, 2018·The Journal of Clinical Investigation·Dmitriy ZamarinJedd D Wolchok
Mar 27, 2018·Molecular Therapy : the Journal of the American Society of Gene Therapy·Richard G Vile
Apr 27, 2018·Nature Reviews. Cancer·Kwame Twumasi-BoatengBrad H Nelson
Jun 29, 2018·Journal of Virology·Mirjam SchillingGeorg Kochs
Aug 17, 2018·PLoS Pathogens·Guoxin NiBlossom Damania
Sep 30, 2018·Cancer Immunology Research·Ajit J NirmalTom C Freeman
Dec 28, 2018·Molecular Cancer Research : MCR·Nina Marí Gual Pimenta de QueirozGlen N Barber
Feb 26, 2019·Medical Microbiology and Immunology·Markus StempelMelanie M Brinkmann
Mar 9, 2019·Science·Andrea Ablasser, Zhijian J Chen
Apr 17, 2019·Molecular Therapy Oncolytics·Joel LeeKevin A Cassady
May 10, 2019·Oncoimmunology·Maria Eugenia Davola, Karen Louise Mossman
May 14, 2019·Molecular Therapy Oncolytics·Venkatesh SivanandamSusanne G Warner
Jul 20, 2019·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Luke RussellRosa Maria Diaz
Aug 30, 2019·Cancer Immunology Research·Rana FalahatJames J Mulé
Oct 31, 2019·Cell Reports·Linda SchadtMaries van den Broek

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Citations

Feb 10, 2021·Cancers·Eftychia StavrakakiMartine L M Lamfers
Jan 10, 2021·International Journal of Molecular Sciences·Guendalina FroechlichNicola Zambrano
Mar 7, 2021·International Journal of Molecular Sciences·Evita AthanasiouAthanassios Tsakris
Jul 3, 2021·International Journal of Molecular Sciences·Elena Shklovskaya, Helen Rizos
Aug 11, 2021·Viruses·Chase KangasBin He

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Methods Mentioned

BETA
FACS
PCR
xenografts
Assay
ELISA

Clinical Trials Mentioned

NCT02675439
NCT03937141

Software Mentioned

nSolver Analysis
GraphPad Prism
nCounter
STRING
Origene

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