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

12. März 2020

Brenner E1, Schörg BF2, Ahmetlić F3,4, Wieder T1, Hilke FJ5, Simon N1, Schroeder C5, Demidov G5, Riedel T3, Fehrenbacher B1, Schaller M1, Forschner A1, Eigentler T1, Niessner H1, Sinnberg T1, Böhm KS1, Hömberg N3,4, Braumüller H1, Dauch D6,7, Zwirner S6, Zender L6,7,8, Sonanini D2,6, Geishauser A34, Bauer J1, Eichner M9, Jarick KJ10, Beilhack A10, Biskup S8,11, Döcker D1,11, Schadendorf D7,12, Quintanilla-Martinez L8,13, Pichler BJ2,8, Kneilling M1,2,8, Mocikat R3,4, Röcken M14,15,16.


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.