Credit: Macmillan Australia

CD4+ T helper 1 (TH1) cells are associated with antitumour immune responses that induce growth arrest, rather than eradication, of tumour cells. But the mechanism by which tumour growth is arrested remains unknown.

TH1 cell-derived cytokines IFNγ and TNF can induce tumour cell senescence

RIP-Tag2 mice develop pancreatic tumours owing to the expression of SV40 large T antigen in pancreatic islet cells. Using this mouse model it has previously been shown that large T antigen-specific TH1 cells secreting the cytokines interferon-γ (IFNγ) and tumour necrosis factor (TNF) attenuate the growth of pancreatic tumours without inducing tumour cell death, which increases the survival of these mice. This effect on pancreatic tumour growth was dependent on the infiltration of IFNγ- and TNF-secreting TH1 cells and the expression of TNF receptor 1 (TNFR1) by the pancreatic tumour cells. Extending these observations, Braumüller, Wieder and colleagues showed that tumour cells isolated from pancreatic tumours exposed to large T antigen-specific TH1 cells in vivo did not proliferate for six passages in vitro. In addition, culturing pancreatic tumour cells from the RIP-Tag2 mice with IFNγ and TNF increased the fraction of cells in G0 phase and G1 phase, without increasing the fraction of apoptotic cells. This indicates that TH1 cell-derived IFNγ and TNF induce tumour cell senescence, which is a long-lasting growth arrest. Indeed, IFNγ and TNF induced markers of senescence in RIP-Tag2 pancreatic tumour cells in vitro.

Next, the authors sought to characterize the mechanism of senescence induction. Through the activation of their respective receptors and subsequent downstream signalling, IFNγ and TNF induce the expression of the transcription factor JUNB, which in turn induces the expression of INK4A (a known inducer of senescence). The authors found that INK4A expression was induced in RIP-Tag2 pancreatic tumour cells that were treated with IFNγ and TNF, and in pancreatic tumour cells that were exposed to large T antigen-specific TH1 cells in vivo. Knockdown of INK4A expression in pancreatic tumour cells prevented the induction of senescence in vitro, and the induction of senescence was also shown to be dependent on TNFR1 expression by the tumour cells in vitro and in vivo. The authors also showed that pancreatic tumour cells (which were isolated from RIP-Tag2 tumours exposed to large T antigen-specific TH1 cells) implanted subcutaneously into NOD-SCID Il2rg−/− (NSG) mice failed to generate tumours. Finally, IFNγ and TNF induced the growth arrest of several types of cancer cell in vitro, including mammary tumour cells from mice expressing polyoma middle T antigen (PyMT), primary human melanoma and sarcoma cells, and various cancer cell lines expressing IFNγ receptor and TNFR1.

These data indicate that the TH1 cell-derived cytokines IFNγ and TNF can induce tumour cell senescence, providing a mechanistic explanation for the antitumour effects of these cells and a rationale for the continued development of tumour-specific TH1 cells for anticancer therapy.

This article is modified from the original in Nature Rev. Cancer (doi:10.1038/nrc3474).