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

Braegelmann J, Lorenz C, Borchmann S, Nishii K, Wegner J, Meder L, Ostendorp J, Ast DF, Heimsoeth A, Nakasuka T, Hirabae A, Okawa S, Dammert MA, Plenker D, Klein S, Lohneis P, Gu J, Godfrey LK, Forster J, Trajkovic-Arsic M, Zillinger T, Haarmann M, Quaas A, Lennartz S, Schmiel M, D'Rozario J, Thomas ES, Li H, Schmitt CA, George J, Thomas RK, Von Karstedt S, Hartmann G, Buettner R, Ullrich RT, Siveke JT, Ohashi K, Schlee M, Sos ML (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 12

Article Number: 5505

Journal Issue: 1

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.

Authors with CRIS profile

Lydia Meder

Involved external institutions

Universität zu Köln DE Germany (DE) Okayama University / 岡山大学 JP Japan (JP) Cold Spring Harbor Laboratory US United States (USA) (US) Universitätsklinikum Essen DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Universitätsklinikum Bonn DE Germany (DE) Crown Bioscience US United States (USA) (US) Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

APA:

Braegelmann, J., Lorenz, C., Borchmann, S., Nishii, K., Wegner, J., Meder, L.,... Sos, M.L. (2021). MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. Nature Communications, 12(1). https://dx.doi.org/10.1038/s41467-021-25728-8

MLA:

Braegelmann, Johannes, et al. "MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I." Nature Communications 12.1 (2021).

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