T-helper-1-cell cytokines tumour necrosis factor and interferon-γ are shown to drive tumour cells into senescence in a mouse model of β-cell carcinoma and human carcinoma cells. Well-defined cell-death mechanisms such as cytolysis and apoptosis are known to be involved in the destruction and clearance of cancer cells, yet how the immune system actually arrests cancer cell proliferation remains unclear. Using mice with Tag-induced cancers, in which T-helper-1 (TH1) cell immunity doubles the lifespan, Martin Röcken and colleagues demonstrate that adaptive immunity mediated by the TH1 cytokines interferon-γ and tumour necrosis factor (TNF) directly induces senescence in cancers. Interferon- and TNF-induced senescence protects even against endogenous cancers that develop through transgenic expression of an oncogene, suggesting that it may be of broad relevance for cancer control. Cancer control by adaptive immunity involves a number of defined death1,2,3,4,5,6,7,8 and clearance9,10,11 mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation1,2,3,4,5,12,13. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence9,10,11,14,15,16,17, 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 control18,19. When combined, IFN-γ 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-γ- and TNFR1-dependent senescence. Conversely, Tnfr1−/−Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.

T-helper-1-cell cytokines drive cancer into senescence