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

(Braumüller H

 et al., Nature. 2013 Feb 21;494(7437):361-5)

Speaker: Meng-Hsuan Tsai (蔡孟暄)                    Time: 15:00~16:00, Apr. 24, 2013

Commentator: Dr. Li-Jin Hsu (徐麗君老師)       Place: Room 601

Abstract

Though CD8⁺ cytotoxic T lymphocytes (CTLs) are considered as important effectors for cancer immunotherapies, the critical roles of CD4⁺ T-helper 1 (T_H1) cells in cancer control have also been recognized. Interestingly, with undefined mechanisms, the anti-tumor T_H1 cells may not kill tumor cells but cause tumor dormancy instead. In this study, the authors defined the underlying mechanism by using a mouse model of where Simian virus 40 large T antigen (Tag) specifically induces pancreatic β-cell cancers. They previously show that Tag-specific T_H1 cells limit the tumor growth and this effect depends on T_H1-produced interferon-γ (IFN-γ) and tumor necrosis factor (TNF). Following this clue, here they found that treatment of β-cancer cells with IFN-γ and TNF caused cell cycle arrest in G1/G0 without inducing cell apoptosis. These arresting cancer cells showed several characteristics of cellular senescence, including senescence-associated β-galactosidase activity, phosphorylated heterochromatin protein 1γ, induction of p16INK4a, and hypophosphorylation of Rb. The cancer cell senescence induced by IFN-γ and TNF required p16, STAT1 and TNFR1.In vivo, Tag-specific T_H1 cells induced growth arrest and senescence of Tag-expressing β-cancer cells, the same as IFN-γ and TNF did in vitro, and the senescent cancer cells showed permanent growth arrest even after transfer into the environment without IFN-γ and TNF. By contrast, Tnfr1^-/- β-cancer cells were refractory to the anti-tumor effect of T_H1 cells. In addition, IFN-γ and TNF induced senescence in many other cancers, suggesting therapeutic significance of the T_H1 cytokines for broad cancer targets.

Reference

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