TY - JOUR
T1 - MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I
AU - Brägelmann, Johannes
AU - Lorenz, Carina
AU - Borchmann, Sven
AU - Nishii, Kazuya
AU - Wegner, Julia
AU - Meder, Lydia
AU - Ostendorp, Jenny
AU - Ast, David F.
AU - Heimsoeth, Alena
AU - Nakasuka, Takamasa
AU - Hirabae, Atsuko
AU - Okawa, Sachi
AU - Dammert, Marcel A.
AU - Plenker, Dennis
AU - Klein, Sebastian
AU - Lohneis, Philipp
AU - Gu, Jianing
AU - Godfrey, Laura K.
AU - Forster, Jan
AU - Trajkovic-Arsic, Marija
AU - Zillinger, Thomas
AU - Haarmann, Mareike
AU - Quaas, Alexander
AU - Lennartz, Stefanie
AU - Schmiel, Marcel
AU - D’Rozario, Joshua
AU - Thomas, Emily S.
AU - Li, Henry
AU - Schmitt, Clemens A.
AU - George, Julie
AU - Thomas, Roman K.
AU - von Karstedt, Silvia
AU - Hartmann, Gunther
AU - Büttner, Reinhard
AU - Ullrich, Roland T.
AU - Siveke, Jens T.
AU - Ohashi, Kadoaki
AU - Schlee, Martin
AU - Sos, Martin L.
N1 - Funding Information:
The CRISPR-engineered Lewis Lung Carcinoma cell lines were a kind gift from Julian Downward. lentiCRISPR v2 was a gift from Feng Zhang (Addgene plasmid # 52961). The authors thank CeGaT GmbH (Tübingen) for RNA-sequencing of murine PDAC cell lines. This work was supported by the Deutsche Krebshilfe (70113009 to R.T.U.; 70113129 to C.L.; 70112888 to M.L.S., 70112505 and 70113835 to J.T.S., Max-Eder-Junior Research Group 701125509 to S.vK., Mildred Scheel Nachwuchszentrum Grant 70113307 to D.A. and J.B.), by the Nachwuchsforschungsgruppen-NRW (1411ng005 to R.T.U.), the Japan Society for the Promotion of Science(JSPS) (Grant-in-Aid for Scientific Research (B) 19K08625 to K.O.), the European Union (Erasmus Fellowship to E.S.T.), the Else Kröner Fresenius Stiftung (Memorial Grant 2018_EKMS.35 to J.B.; 2016‐Kolleg‐ 19 to S.K. and S.B.), the Frauke Weiskam + Christel Ruranski Foundation (S.B.), German Research Foundation (DFG) (PL 894/1-1 to D.P.; SCHL1930/1-2, TRR237; Excellence Cluster ImmunoSensation to M.S. and G.H., SFB670 to G.H., CRC1399 Project-ID 413326622 to M.L.S., R.K.T., S.vK., J.G., and R.B., SI1549/3-1 (KFO337; PhenoTime) to J.T.S.), the German Cancer Consortium (DKTK) to J.T.S., and the Bundesministerium für Bildung und Forschung (eMed consortium grant 01ZX1901A to S.vK., R.K.T., J.G., and M.L.S.; 01ZX1406 to M.L.S.), by the Fritz Thyssen Foundation (10.19.2.025MN to M.L.S.) and the German federal state North Rhine Westphalia (NRW) as part of the EFRE initiative (EFRE-0800397 to M.L.S., R.K.T., and R.B.).
Funding Information:
M.L.S. is a founder and shareholder of PearlRiver Bio (now part of Centessa Pharmaceuticals) and received consulting honoraria from PearlRiver Bio. M.L.S. receives research funding from PearlRiver Bio and Novartis. R.B. is an employee of Targos Molecular Pathology. H.L. is an employee of CrownBiosciences. G.H. is co‐founder of Rigontec GmbH. M.S. is listed as inventor on a patent application covering RIG-I activating structures. R.K.T. is founder of PearlRiver Bio (now part of Centessa Pharmaceuticals), founder of NEO New Oncology (now part of Siemens Healthcare), consulting honoraria from PearlRiver Bio and NEO New Oncology. K.O. received research funding from Boehringer Ingelheim, Novartis, AstraZeneca, Eli Lilly, and Daiichi-Sankyo outside the submitted work. K.O. reports honoraria from AstraZeneca, MSD and Chugai pharmaceutical outside the submitted work. The other authors declare no competing interests.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85115437225&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25728-8
DO - 10.1038/s41467-021-25728-8
M3 - Article
C2 - 34535668
AN - SCOPUS:85115437225
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5505
ER -
