Journal Article

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

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

2020

Overview

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. The growth of cancer cells can be stably arrested by cytokine-induced senescence. Here, the authors show that cancers with defects in senescence-inducing cell cycle regulator pathways are resistant to immune checkpoint blockade.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/21 / 13/31 / 13/51 / 14 / 14/28 / 45 / 45/23 / 45/77 / 45/88 / 49 / 49/39 / 59 / 631/250/251 / 631/67/1059/2325 / 631/67/1244 / 64 / 64/60 / 82/51 / 96/21 / 96/31 / Animals / Antigens, Neoplasm - genetics / Antigens, Neoplasm - metabolism / Cancer / Cell activation / Cell Cycle / Cell Line, Tumor / Cellular Senescence / Clonal deletion / Cyclin-Dependent Kinase Inhibitor p16 - metabolism / Cyclin-dependent kinase inhibitor p21 / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Cytokines / Humanities and Social Sciences / Humans / Immune checkpoint / Immunotherapy / INK4a protein / Interferon / Interferons - metabolism / Ki-67 Antigen - metabolism / Lymph Nodes - pathology / Lymphocytes / Lymphocytes T / Melanoma / Melanoma - immunology / Melanoma - pathology / Melanoma - therapy / Melanoma - ultrastructure / Metastases / Metastasis / Mice / Mice, Inbred C57BL / multidisciplinary / p16 Protein / Regulators / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Senescence / STAT1 Transcription Factor - metabolism / Survival Analysis / Tumor Burden / Tumors