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bioRxiv · 10.1101/339580

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

Wolkers, M. C.·Salerno, F.·Guislain, A.·Freen-van Heeren, J. J.·Nicolet, B. P.·Young, H. A.
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Abstract

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 3untranslated 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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Wolkers, M. C., Salerno, F., Guislain, A., Freen-van Heeren, J. J., Nicolet, B. P., Young, H. A.. 2018-06-05. Critical role of post-transcriptional regulation for IFN-γ in tumor-infiltrating T cells. https://doi.org/10.1101/339580

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