Critical role of post-transcriptional regulation for IFN-gamma in tumor-infiltrating T cells

Protective T cell responses against tumors require the production of Interferon gamma (IFN-gamma). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-gamma and therefore fail to clear malignant cells. Dissecting the underlying mechanisms that block cytokine production is thus key for improving T cell products. Here we show that although TILs express substantial levels of Ifng mRNA, post-transcriptional mechanisms impede the production of IFN-gamma protein due to loss of mRNA stability. CD28 triggering, but not PD1 blocking antibodies, effectively restores the stability of Ifng mRNA. Intriguingly, TILs devoid of AU-rich elements within the 3' untranslated region maintain stabilized Ifng mRNA and produce more IFN-gamma protein than wild-type TILs. This sustained IFN-gamma production translates into effective suppression of tumor outgrowth, which is almost exclusively mediated by direct effects on the tumor cells. We therefore conclude that post-transcriptional mechanisms could be modulated to potentiate effective T cell therapies in cancer.

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