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

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-14987-6

2041-1723

Ellen Brenner, Barbara F. Schörg, Fatima Ahmetlić, Thomas Wieder, Franz J. Hilke, Nadine Simon, Christopher Schroeder, German Demidov, Tanja Riedel, Birgit Fehrenbacher, Martin Schaller, Andrea Forschner, Thomas Eigentler, Heike Niessner, Tobias Sinnberg, Katharina 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‐Martínez, Bernd J. Pichler, Manfred Kneilling, Ralph Mocikat, Martin Röcken,

Immunotherapy and Immune Responses

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 p16 Ink4a /p19 Arf ( Cdkn2a ) or p21 Cip1 ( 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.