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

Brägelmann, Johannes, Lorenz, Carina, Borchmann, Sven, Nishii, Kazuya, Wegner, Julia, Meder, Lydia, Ostendorp, Jenny, Ast, David F, Heimsoeth, Alena, Nakasuka, Takamasa, Hirabae, Atsuko, Okawa, Sachi, Dammert, Marcel A, Plenker, Dennis, Klein, Sebastian, Lohneis, Philipp, Gu, Jianing, Godfrey, Laura K, Forster, Jan, Trajkovic-Arsic, Marija, Zillinger, Thomas, Haarmann, Mareike, Quaas, Alexander, Lennartz, Stefanie, Schmiel, Marcel, D'Rozario, Joshua, Thomas, Emily S, Li, Henry, Schmitt, Clemens A, George, Julie, Thomas, Roman K, von Karstedt, Silvia, Hartmann, Gunther, Büttner, Reinhard, Ullrich, Roland T, Siveke, Jens T, Ohashi, Kadoaki, Schlee, Martin, Sos, Martin L (September 2021) MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. Nature Communications, 12 (1). p. 5505. ISSN 2041-1723

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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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > inflammation > cytokines bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell diseases & disorders > inflammation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase diseases & disorders > cancer > cancer types > lung cancer organism description > animal > mammal bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Mitogen-activated protein kinase organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogenes organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction organs, tissues, organelles, cell types and functions > tissues types and functions diseases & disorders > cancer > cancer types
CSHL Authors:	Plenker, Dennis
Communities:	CSHL labs > Tuveson lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	17 September 2021
Date Deposited:	23 Sep 2021 14:14
Last Modified:	09 Feb 2024 21:11
PMCID:	PMC8448826
URI:	https://repository.cshl.edu/id/eprint/40358

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