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

Author:

Brenner Ellen,Schörg Barbara F.ORCID,Ahmetlić Fatima,Wieder Thomas,Hilke Franz Joachim,Simon Nadine,Schroeder Christopher,Demidov GermanORCID,Riedel Tanja,Fehrenbacher Birgit,Schaller Martin,Forschner Andrea,Eigentler Thomas,Niessner Heike,Sinnberg TobiasORCID,Böhm Katharina S.,Hömberg Nadine,Braumüller Heidi,Dauch Daniel,Zwirner Stefan,Zender Lars,Sonanini Dominik,Geishauser Albert,Bauer Jürgen,Eichner Martin,Jarick Katja J.ORCID,Beilhack Andreas,Biskup Saskia,Döcker Dennis,Schadendorf DirkORCID,Quintanilla-Martinez Leticia,Pichler Bernd J.,Kneilling Manfred,Mocikat Ralph,Röcken Martin

Abstract

AbstractImmune 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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