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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URL: https://www.ncbi.nlm.nih.gov/pubmed/34535668
DOI: 10.1038/s41467-021-25728-8

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: 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 > cancer > cancer types > lung cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 17 September 2021
Date Deposited: 23 Sep 2021 14:14
Last Modified: 06 Oct 2021 15:34
PMCID: PMC8448826
URI: https://repository.cshl.edu/id/eprint/40358

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