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

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.

SUBMITTER: Brenner E

PROVIDER: S-EPMC7067802 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Brenner Ellen E Schörg Barbara F BF Ahmetlić Fatima F Wieder Thomas T Hilke Franz Joachim FJ Simon Nadine N Schroeder Christopher C Demidov German G Riedel Tanja T Fehrenbacher Birgit B Schaller Martin M Forschner Andrea A Eigentler Thomas T Niessner Heike H Sinnberg Tobias T Böhm Katharina S KS Hömberg Nadine N Braumüller Heidi H Dauch Daniel D Zwirner Stefan S Zender Lars L Sonanini Dominik D Geishauser Albert A Bauer Jürgen J Eichner Martin M Jarick Katja J KJ Beilhack Andreas A Biskup Saskia S Döcker Dennis D Schadendorf Dirk D Quintanilla-Martinez Leticia L Pichler Bernd J BJ Kneilling Manfred M Mocikat Ralph R Röcken Martin M

Nature communications 20200312 1

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, tha ...[more]

PMID: 32165639

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

Publications

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

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