IFNγ in the Tumour Microenvironment as a Potential Senescence Inducer and Epigenetic Modifier

IFNγ, a crucial cytokine mediating anti-tumour immunity, also exerts direct effects on tumour cells; some of them may be related to oxidative stress. First, we focused on a potential role of IFNγ as an epigenetic modifier. We have investigated the mechanisms by which IFNγ restores expression of the antigen-presenting machinery genes, located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7), in several MHC class I-deficient murine tumour cell lines. Activation of these genes and MHC class I upregulation on the cell surface was strongly associated with DNA demethylation and increased histone H3 acetylation in the promoter regions of the APM genes. So far, our data suggest that this IFNγ-induced DNA demethylation is an active process. In another set of experiments, we demonstrated in vitro that Th1 cytokines IFNγ and TNFα were able to induce cellular senescence in B16 melanoma but not in TC-1 tumour cells. This cytokine-induced senescence was associated with ROS production and NOX4 expression in B16 cells induced via the TGFβ/SMAD pathway. Collectively, our results demonstrate some novel mechanisms by which IFNγ can mediate tumour cell interactions with the immune system within the tumour microenvironment and cast more light on the role of the IFNγ signalling pathway in tumour cell proliferation regulation.

This work was supported by the NT 14461 grant from the Grant Agency of the Ministry of Health of the Czech Republic, grant No. 15-24769S from the Czech Science Foundation (GACR) and by the Institutional Grant (Project RVO 68378050).