Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours

Ellen Brenner, Barbara F. Schörg, Fatima Ahmetlić, Thomas Wieder, Franz Joachim Hilke, Nadine Simon, Christopher Schroeder, German Demidov, Tanja Riedel, Birgit Fehrenbacher, Martin Schaller, Andrea Forschner, Thomas Eigentler, Heike Niessner, Tobias Sinnberg, Katharina S. Böhm, Nadine Hömberg, Heidi Braumüller, Daniel Dauch, Stefan Zwirner, Lars Zender, Dominik Sonanini, Albert Geishauser, Jürgen Bauer, Martin Eichner, Katja J. Jarick, Andreas Beilhack, Saskia Biskup, Dennis Döcker, Dirk Schadendorf, Leticia Quintanilla-Martinez, Bernd J. Pichler, Manfred Kneilling, Ralph Mocikat and Martin Röcken ()
Additional contact information
Ellen Brenner: University of Tübingen
Barbara F. Schörg: University of Tübingen
Fatima Ahmetlić: Institut für Molekulare Immunologie, Helmholtz-Zentrum München
Thomas Wieder: University of Tübingen
Franz Joachim Hilke: University of Tübingen
Nadine Simon: University of Tübingen
Christopher Schroeder: University of Tübingen
German Demidov: University of Tübingen
Tanja Riedel: Institut für Molekulare Immunologie, Helmholtz-Zentrum München
Birgit Fehrenbacher: University of Tübingen
Martin Schaller: University of Tübingen
Andrea Forschner: University of Tübingen
Thomas Eigentler: University of Tübingen
Heike Niessner: University of Tübingen
Tobias Sinnberg: University of Tübingen
Katharina S. Böhm: University of Tübingen
Nadine Hömberg: Institut für Molekulare Immunologie, Helmholtz-Zentrum München
Heidi Braumüller: University of Tübingen
Daniel Dauch: University Hospital Tübingen
Stefan Zwirner: University Hospital Tübingen
Lars Zender: University Hospital Tübingen
Dominik Sonanini: University of Tübingen
Albert Geishauser: Institut für Molekulare Immunologie, Helmholtz-Zentrum München
Jürgen Bauer: University of Tübingen
Martin Eichner: Institute of Clinical Epidemiology and Applied Biometry, University of Tübingen
Katja J. Jarick: Würzburg University
Andreas Beilhack: Würzburg University
Saskia Biskup: Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”
Dennis Döcker: University of Tübingen
Dirk Schadendorf: German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ)
Leticia Quintanilla-Martinez: Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”
Bernd J. Pichler: University of Tübingen
Manfred Kneilling: University of Tübingen
Ralph Mocikat: Institut für Molekulare Immunologie, Helmholtz-Zentrum München
Martin Röcken: University of Tübingen

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: Abstract Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.

Date: 2020
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DOI: 10.1038/s41467-020-14987-6

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