Too Much Of A Good Thing: Ifn-I, Dendritic Cells, And Cancer
JOURNAL OF IMMUNOLOGY(2020)
Abstract
Abstract To prime T cells to fight cancer, dendritic cells (DCs) require Type I Interferon (IFN-I) signaling. IFN-I signaling induces the transcription and translation of Interferon Stimulated Genes (ISGs), including strong induction of Usp18, which dampens further IFN-I signaling. We hypothesized that increasing IFN-I signals to DCs in vivo via conditional Usp18 deletion would enhance the ability of DCs to prime T cells, augmenting their anti-tumor activity. To test this, we used Usp18fl/fl x CD11c-cre mice and the syngeneic B16F10 melanoma model. Surprisingly, tumors grew more quickly in Usp18fl/fl x CD11c-cre mice, and intratumoral T cells were less functional post-priming by Usp18-deficient DCs. This functional decrease was coupled with an accelerated effector differentiation marked by early loss of the stem cell-like factor TCF-1. These data suggest that Usp18-deficient DCs expedite terminal effector T cell differentiation, resulting in suppressed effector functionality at later time points. Consistent with this T cell dysfunction, intratumoral STING agonism was less effective at controlling tumors in Usp18fl/fl x CD11c-Cre mice than Usp18fl/fl littermate controls. To understand the molecular drivers of these changes, we profiled DCs with tandem mass tag (TMT) mass spectrometry. We found that Usp18-deficient DCs exhibit deficiencies in mitochondrial function and cysteine biosynthesis, potentially driving their altered ability to prime T cells. Overall, this work highlights the importance of stringent IFN-I signaling regulation for mounting optimal immune responses to cancer. Our findings also identify DC-intrinsic Usp18 expression as a potential biomarker for predicting patient responsiveness to STING agonist therapy.
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Key words
dendritic cells,cancer
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