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T-helper-1-cell cytokines drive cancer into senescence.
Braumuller, Heidi 1,*; Wieder, Thomas 1,*; Brenner, Ellen 1; Amann, Sonja 1[latin sharp s]; Hahn, Matthias 1; Alkhaled, Mohammed 2; Schilbach, Karin 2; Essmann, Frank 3; Kneilling, Manfred 1; Griessinger, Christoph 1,4; Ranta, Felicia 5; Ullrich, Susanne 5; Mocikat, Ralph 6; Braungart, Kilian 1; Mehra, Tarun 1; Fehrenbacher, Birgit 1; Berdel, Julia 1; Niessner, Heike 1; Meier, Friedegund 1; van den Broek, Maries 7; Haring, Hans-Ulrich 5; Handgretinger, Rupert 2,8; Quintanilla-Martinez, Leticia 9; Fend, Falko 8,9; Pesic, Marina 10; Bauer, Jurgen 1; Zender, Lars 10; Schaller, Martin 1; Schulze-Osthoff, Klaus 3,8; Rocken, Martin 1,8
[Letter] Nature. 494(7437):361-365, February 21, 2013.

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: Cancer control by adaptive immunity involves a number of defined death 1,2,3,4,5,6,7,8 and clearance 9,10,11 mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-[gamma] (IFN-[gamma]) requires additional undefined mechanisms that arrest cancer cell proliferation 1,2,3,4,5,12,13. Here we show that the combined action of the T-helper-1-cell cytokines IFN-[gamma] and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence 9,10,11,14,15,16,17, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control 18,19. When combined, IFN-[gamma] and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-[gamma]- and TNFR1-dependent senescence. Conversely, Tnfr1-/- Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-[gamma] and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.