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RNA N6-methyladenosine-binding protein YTHDFs redundantly attenuate cancer immunity by downregulating IFN-γ signaling in gastric cancer [RNA-Seq]

ABSTRACT: Gastric cancer (GC) is a prominent public health issue, especially in East Asia, and holds the fourth rank in terms of cancer mortality. While immunotherapy holds potential as a treatment avenue for GC, resistance to immune checkpoint inhibitors (ICIs) remains an obstacle. One resistance mechanism involves defects in IFN-γ signaling, where IFN-γ is linked to improved responsiveness to ICIs. In this study, we unveiled the role of N6-methyladenosine (m6A) RNA modifications, in the regulation of IFN-γ signaling and the responsiveness to ICIs. The m6A-binding protein YTHDF1 was overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. Overexpression of YTHDF1 impaired the responsiveness to IFN-γ in GC cells, while knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 on IFN-γ responsiveness. RNA immunoprecipitation-sequencing identified that YTHDFs directly targeted the mRNA of IRF1, which is one of master regulators of IFN-γ signaling, leading to reduced RNA stability and consequent downregulation of IFN-γ signaling. Furthermore, in mouse syngeneic tumor models, the depletion of Ythdf1 in cancer cells resulted in reduced tumor growth and heightened tumor infiltrating lymphocytes, which is attributed to the augmentation of IFN-γ signaling. Collectively, our findings highlight how YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation, thus proposing their viability as therapeutic targets in the realm of cancer immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270417 | GEO | 2025/01/29

REPOSITORIES: GEO

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RNA N6-methyladenosine-binding protein YTHDFs redundantly attenuate cancer immunity by downregulating IFN-γ signaling in gastric cancer [RIP-Seq]

Project description:Gastric cancer (GC) is a prominent public health issue, especially in East Asia, and holds the fourth rank in terms of cancer mortality. While immunotherapy holds potential as a treatment avenue for GC, resistance to immune checkpoint inhibitors (ICIs) remains an obstacle. One resistance mechanism involves defects in IFN-γ signaling, where IFN-γ is linked to improved responsiveness to ICIs. In this study, we unveiled the role of N6-methyladenosine (m6A) RNA modifications, in the regulation of IFN-γ signaling and the responsiveness to ICIs. The m6A-binding protein YTHDF1 was overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. Overexpression of YTHDF1 impaired the responsiveness to IFN-γ in GC cells, while knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 on IFN-γ responsiveness. RNA immunoprecipitation-sequencing identified that YTHDFs directly targeted the mRNA of IRF1, which is one of master regulators of IFN-γ signaling, leading to reduced RNA stability and consequent downregulation of IFN-γ signaling. Furthermore, in mouse syngeneic tumor models, the depletion of Ythdf1 in cancer cells resulted in reduced tumor growth and heightened tumor infiltrating lymphocytes, which is attributed to the augmentation of IFN-γ signaling. Collectively, our findings highlight how YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation, thus proposing their viability as therapeutic targets in the realm of cancer immunotherapy.

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2023-02-02 | PXD035347 | Pride

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Human IRF1 governs phagocytic IFN-γ immunity to mycobacteria but not cell-intrinsic IFN-a/b immunity to viruses [scRNAseq]

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Oncogenic Ras inhibits IRF1 to promote viral oncolysis

Project description:Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1−/− MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis.

2014-11-13 | GSE49469 | GEO

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