T_H1 Immune Signaling Induces Cancer Cell Senescence

Stimulation of tumor-specific CD4-positive T-helper 1 (T_H1) adaptive immune cells limits cancer cell growth and is correlated with tumor regression. This anticancer effect requires production of the T_H1 cytokines IFN-γ and TNF but is independent of cytotoxic T lymphocytes and cancer cell apoptosis. To further elucidate the mechanisms by which T_H1 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. T_H1 cytokine-driven senescence was mediated by enhanced expression of cyclin-dependent kinase inhibitor 2A (also known as p16^INK4A) 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 T_H1 cells activated p16^INK4A 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 T_H1 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 T_H1 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].