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Oncoimmunology. 2018 Oct 22;8(2):e1532762. doi: 10.1080/2162402X.2018.1532762. eCollection 2019.

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

Author information

1
Department of Hematopoiesis, Sanquin Research/AMC Landsteiner Laboratory, Amsterdam, The Netherlands.
2
Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, MD, USA.

Abstract

Protective T cell responses against tumors require the production of Interferon gamma (IFN-γ). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-γ 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-γ 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-γ protein than wild-type TILs. This sustained IFN-γ 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.

KEYWORDS:

B16 melanoma; CD28; IFN-γ; PD-1; Tumor-infiltrating T cells; mRNA stability; post-transcriptional regulation

PMID:
30713785
PMCID:
PMC6343783
[Available on 2019-10-22]
DOI:
10.1080/2162402X.2018.1532762

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