MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

Johannes Brägelmann (), Carina Lorenz, Sven Borchmann, Kazuya Nishii, Julia Wegner, Lydia Meder, Jenny Ostendorp, David F. Ast, Alena Heimsoeth, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Marcel A. Dammert, Dennis Plenker, Sebastian Klein, Philipp Lohneis, Jianing Gu, Laura K. Godfrey, Jan Forster, Marija Trajkovic-Arsic, Thomas Zillinger, Mareike Haarmann, Alexander Quaas, Stefanie Lennartz, Marcel Schmiel, Joshua D’Rozario, Emily S. Thomas, Henry Li, Clemens A. Schmitt, Julie George, Roman K. Thomas, Silvia Karstedt, Gunther Hartmann, Reinhard Büttner, Roland T. Ullrich, Jens T. Siveke, Kadoaki Ohashi, Martin Schlee and Martin L. Sos ()
Additional contact information
Johannes Brägelmann: University of Cologne
Carina Lorenz: University of Cologne
Sven Borchmann: University of Cologne
Kazuya Nishii: Dentistry and Pharmaceutical Sciences
Julia Wegner: University Hospital Bonn
Lydia Meder: University of Cologne
Jenny Ostendorp: University of Cologne
David F. Ast: University of Cologne
Alena Heimsoeth: University of Cologne
Takamasa Nakasuka: Dentistry and Pharmaceutical Sciences
Atsuko Hirabae: Dentistry and Pharmaceutical Sciences
Sachi Okawa: Dentistry and Pharmaceutical Sciences
Marcel A. Dammert: University of Cologne
Dennis Plenker: Cold Spring Harbor Laboratory
Sebastian Klein: University of Cologne
Philipp Lohneis: University of Cologne
Jianing Gu: University Hospital Essen
Laura K. Godfrey: University Hospital Essen
Jan Forster: German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ
Marija Trajkovic-Arsic: University Hospital Essen
Thomas Zillinger: University Hospital Bonn
Mareike Haarmann: University of Cologne
Alexander Quaas: University of Cologne
Stefanie Lennartz: University of Cologne
Marcel Schmiel: University of Cologne
Joshua D’Rozario: University of Cologne
Emily S. Thomas: University of Cologne
Henry Li: Crown Bioscience
Clemens A. Schmitt: Charité - University Medical Center, Virchow Campus, and Molekulares Krebsforschungszentrum
Julie George: University of Cologne
Roman K. Thomas: University of Cologne
Silvia Karstedt: University of Cologne
Gunther Hartmann: University Hospital Bonn
Reinhard Büttner: University of Cologne
Roland T. Ullrich: University of Cologne
Jens T. Siveke: University Hospital Essen
Kadoaki Ohashi: Dentistry and Pharmaceutical Sciences
Martin Schlee: University Hospital Bonn
Martin L. Sos: University of Cologne

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25728-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25728-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25728-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().