Adaptive TH1 immunity arrests tumor growth by triggering IFN-γ- and TNF-dependent senescence.

  • Major finding: Adaptive TH1 immunity arrests tumor growth by triggering IFN-γ- and TNF-dependent senescence.

  • Mechanism: IFN-γ/STAT1 and TNFR1 signaling activate p16INK4A to promote permanent growth arrest.

  • Impact: TH1 cytokine-driven senescence may contribute to tumor dormancy in multiple cancer types.

Stimulation of tumor-specific CD4-positive T-helper 1 (TH1) adaptive immune cells limits cancer cell growth and is correlated with tumor regression. This anticancer effect requires production of the TH1 cytokines IFN-γ and TNF but is independent of cytotoxic T lymphocytes and cancer cell apoptosis. To further elucidate the mechanisms by which TH1 immunity mediates growth arrest, Braumüller and colleagues used a mouse model of β-cell tumorigenesis driven by expression of the Simian virus large T antigen (Tag) in pancreatic islet cells. Combined treatment of β-cancer cells with IFN-γ and TNF resulted in accumulation of cells in the G1/G0 phase of the cell cycle and was associated with epigenetic changes indicative of cellular senescence, including phosphorylation of heterochromatin protein 1γ and trimethylation of histone 3 lysine 9, and with increased senescence-associated β-galactosidase activity. TH1 cytokine-driven senescence was mediated by enhanced expression of cyclin-dependent kinase inhibitor 2A (also known as p16INK4A) and downstream activation of the retinoblastoma (RB) protein in response to IFN-γ and TNF and was dependent on STAT1 and TNF receptor 1 (TNFR1) signaling. Treatment with Tag-specific TH1 cells activated p16INK4A and induced features of senescence in murine β-cell tumors; this growth arrest persisted in isolated β-cancer cells over multiple passages in culture and remained stable after reimplantation of these cells in vivo. In contrast, Tnfr1 deficiency in β-cancer cells conferred resistance to senescence induction by TH1 immunity and facilitated exponential growth in culture and upon transplantation into wild-type recipient mice. Strikingly, IFN-γ and TNF also triggered senescence in multiple cancer cell types and in primary human melanoma and sarcoma cells. These results implicate adaptive TH1 immunity in promoting tumor dormancy and suggest that this may be a common mechanism of immune-mediated growth restriction in cancer.

Braumüller H, Wieder T, Brenner E, Assmann S, Hahn M, Alkhaled M, et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 2013 Feb 3 [Epub ahead of print].