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USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation

ABSTRACT: N6-methyladenosine (m6A) binding protein YTHDF1 is frequently upregulated in various cancers and its depletion enhances the efficacy of immune checkpoint blockade (ICB) therapy. This study reveals that USP5 interacts with YTHDF1, preventing its K11-linked polyubiquitination, thereby stabilizing YTHDF1 and promoting its oncogenic properties. In response to insulin, mTORC1 phosphorylates USP5, facilitating its dimerization and subsequent binding to YTHDF1, while the CUL7-FBXW8 complex promotes its degradation. Notably, YTHDF1 or USP5 deficiency increases PD-L1 expression and impairs immune response gene expression, contributing to immune evasion. Combining USP5 inhibitors with anti-PD-1 therapy enhances antitumor T-cell immunity and improves tumor regression in mouse models. Thus, USP5 may serve as a biomarker for stratifying patients for anti-PD-1 therapy, suggesting a novel strategy of combining USP5 inhibition with PD-(L)1 blockade to enhance cancer treatment efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE278264 | GEO | 2024/12/05

REPOSITORIES: GEO

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USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation

Project description:The N6-methyladenosine (m6A) binding protein YTHDF1 emerges as a frequently upregulated oncogene across various cancer types. Its depletion significantly improves the efficacy of cancer immune checkpoint blockade (ICB) treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of ICB in cancer patients. Here, we report that USP5 interacts with YTHDF1, removing K11-linked polyubiquitination on multiple lysine residues to stabilize YTHDF1, thereby conferring its oncogenic properties. In response to insulin, mTORC1 phosphorylates USP5 at S149, promoting its dimerization. Dimerized USP5 then binds to YTHDF1, preventing its degradation. Conversely, the CUL7-FBXW8 E3 ubiquitin ligase promotes K11-linked polyubiquitination and degradation of YTHDF1. USP5 and FBXW8 thus regulate YTHDF1 ubiquitylation at defined residues through mutually exclusive interactions and opposing activities. Furthermore, deficiency in YTHDF1 or USP5 enhances PD-L1 expression and compromises the expression of multiple immune response-related genes, fostering cancer immune evasion. Remarkably, combining USP5 inhibitor treatment with anti-PD-1 immunotherapy reprograms the antitumor T-cell immunity environment, leading to enhanced tumor regression and markedly improved overall survival rates in mouse tumor models. Therefore, in hepatocellular carcinoma and lung cancer patients, USP5 may serve as a promising biomarker for stratifying individuals for anti-PD-1 therapy. Our findings reveal a ubiquitination-dependent regulation of YTHDF1 protein stability influencing immune response gene expression, suggesting USP5 inhibition combined with PD-(L)1 blockade as a novel and promising strategy for cancer treatment.

2024-12-11 | GSE255922 | GEO

USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation

2024-05-31 | PXD052781 |

USP5 Stabilizes YTHDF1 to Control Cancer Immune Surveillance through mTORC1-mediated Phosphorylation

Project description:The N6-methyladenosine (m6A) binding protein YTHDF1 emerges as a frequently upregulated oncogene across various cancer types. Its depletion significantly improves the efficacy of cancer immune checkpoint blockade (ICB) treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of ICB in cancer patients. Here, we report that USP5 interacts with YTHDF1, removing K11-linked polyubiquitination on multiple lysine residues to stabilize YTHDF1, thereby conferring its oncogenic properties. In response to insulin, mTORC1 phosphorylates USP5 at S149, promoting its dimerization. Dimerized USP5 then binds to YTHDF1, preventing its degradation. Conversely, the CUL7-FBXW8 E3 ubiquitin ligase promotes K11-linked polyubiquitination and degradation of YTHDF1. USP5 and FBXW8 thus regulate YTHDF1 ubiquitylation at defined residues through mutually exclusive interactions and opposing activities. Furthermore, deficiency in YTHDF1 or USP5 enhances PD-L1 expression and compromises the expression of multiple immune response-related genes, fostering cancer immune evasion. Remarkably, combining USP5 inhibitor treatment with anti-PD-L1 immunotherapy reprograms the anti-tumor T-cell immunity environment, leading to enhanced tumor regression and markedly improved overall survival rates in mouse tumor models. Therefore, in hepatocellular carcinoma and lung cancer patients, USP5 may serve as a promising biomarker for stratifying individuals for anti-PD-1 therapy. Our findings reveal a ubiquitination-dependent regulation of YTHDF1 protein stability influencing immune response gene expression, suggesting USP5 inhibition combined with PD-(L)1 blockade as a novel and promising strategy for cancer treatment.

2024-11-14 | PXD057917 |

Nuclear Accumulation of YTHDF1 Regulates mRNA Splicing in the DNA Damage Response

Project description:YTH domain-containing family protein 1 (YTHDF1), a reader of N6-methyladenosine, has been implicated in regulating RNA metabolism in the cytosol. Here we report a role of YTHDF1 within the nucleus in response to genotoxic stress. Upon radiation, YTHDF1 is phosphorylated at serine 182 in an ATR-dependent manner. This phosphorylation inhibits exportin 1-mediated nuclear export of YTHDF1, resulting in its accumulation within the nucleus. Nuclear YTHDF1 enhances the binding capacity of SRSF2 to a group of m6A-modified exons, leading to increased exon inclusion. Specifically, YTHDF1 promotes splicing and expression of DNA repair genes, such as BRCA1 and TP53BP1, thereby mitigating excessive DNA damage. Depletion of YTHDF1 sensitizes cancer cells to radiation treatment. Altogether, our study reveals a crucial role of YTHDF1 in m6A-mediated mRNA splicing in the DNA damage response, proposing it as a potential target for radiation therapy.

2025-03-12 | GSE247891 | GEO

Multi-Omics and Informatics Analysis of FFPE Tissues Derived from Melanoma Patients with Long/Short Responses to Anti-PD1 Therapy Reveals Pathways of Response

Project description:Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed while on anti-PD-1 therapy for 1 year. We identified 263 protein/gene candidates that displayed differential expression, of which 223 were identified via proteomics and 40 via targeted-mRNA analyses. The downstream analyses of expression profiles using MetaCore software demonstrated an enrichment of immune system pathways involved in antigen processing/presentation and cytokine production/signaling. Pathway analyses showed interferon (IFN)-γ-mediated signaling via NF-κB and JAK/STAT pathways to affect immune processes in a cell-specific manner and to interact with the inducible nitric oxide synthase. We review these findings within the context of available literature on the efficacy of anti-PD-1 therapy. The comparison of good and poor responders, using efficacy of PD-1-based therapy at 1 year, elucidated the role of antigen presentation in mediating response or resistance to anti-PD-1 blockade.

2022-04-21 | PXD033340 | Pride

Gene Expression Profiling of human monocytes: Combination Therapy with AntiâCTLA-4 and AntiâPD-1 Leads to Distinct Immunologic Changes In Vivo

Project description:Transcriptome analysis of human peripheral blood monocytes Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) and functional signatures in vivo in purified human T cells and monocytes. RNA extracted from freshly isolated monocytes from peripheral blood of patients treated with either antiâPD-1 (n = 6), antiâCTLA-4 (n = 5), Combo therapy with antiâPD-1 and antiâCTLA-4 concurrently (Combo, n = 6), and Seq antiâPD-1 in patients with prior antiâCTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-16 | E-GEOD-77924 | biostudies-arrayexpress

Gene Expression Profiling of human T cells: Combination Therapy with Antiâ??CTLA-4 and Antiâ??PD-1 Leads to Distinct Immunologic Changes In Vivo

Project description:Transcriptome analysis of human peripheral blood T cells Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) andfunctional signatures in vivo in purified human T cells. RNA extracted from freshly isolated T cells from peripheral blood of patients treated with either antiâ??PD-1 (n = 6), antiâ??CTLA-4 (n = 5), Combo therapy with antiâ??PD-1 and antiâ??CTLA-4 concurrently (Combo, n = 6), and Seq antiâ??PD-1 in patients with prior antiâ??CTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-10 | E-GEOD-77714 | biostudies-arrayexpress

YTHDF1 Amplifies Wnt/β-Catenin Signaling to Promote Intestinal Stemness

Project description:Wnt/β-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating β-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment β-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy.

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RNA-Seq of hamster PDAC cancer (HapT1 cell line) biopsies taken after treatment with either an IgG control or new hamster specific anti-PD-L1 monoclonal antibody.

Project description:1. The experiment was performed to assess if the newly discovered Syrian hamster specific anti-PD-L1 antibody could induce a biologically relevant change in transcriptome profile in the tumours. This would confirm that the antibody has functional properties. In the larger picture, the Syrian Hamster model is favored over the mouse model for the development of vaccines and testing of oncolytic viruses/immunotherapies. This is because the model is semi permissive to virus replication compared to the mouse model. We can therefore more reliably assess the efficacy of oncolytic virotherapies, mainly oncolysis and promoter specific transgene expression. Moreover, we wanted to test potential improvements to treatment outcomes when combining oncolytic virotherapy and immune checkpoint blockade. However, there are not many commercially available research tools specific to the Syrian Hamster. This is why we developed an in vivo compatible immune checkpoint inhibitor so that we could assess the combination therapy in the Syrian hamster model. Lastly, we also wanted to validate if we could assess the efficacy of the immunotherapies using biopsies from hamsters to remove unnecessary use of animals. 2. To do this, we engrafted one PDAC tumours on the right flank of Syrian hamsters using 5 x10E+6 HapT1 cells grown in culture. When tumours reached 4-5mm in diameter, the hamsters were injected intraperitoneally with either 300ug of IgG2a control or anti-PD-L1 (clone;11B12-1). Hamsters were treated 8 times and a tumour biopsy was taken one day before the last treatment. The biopsy was immediately stored in RNA-later until extraction with RNA mini kit (Qiagen).

2023-01-30 | E-MTAB-12297 | biostudies-arrayexpress

Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy

Project description:Results of combining radiotherapy/chemoradiotherapy and immune checkpoint blockade have been disappointing in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). For such a potentially radiocurable disease, there remains an imperative to explore novel combination approaches. Here, we show that combining ATR inhibition with radiotherapy (ATRi/RT) increases the frequency of activated NKG2A/PD-1 double-positive T cells in animal models of HNSCC. Addition of dual anti-NKG2A/-PD-L1 blockade to ATRi/RT in the adjuvant, post-radiotherapy setting induces a robust antitumour response. Efficacy of the combination relies on CD40/CD40L costimulatory-mediated infiltration of activated/proliferative/memory CD8 and CD4 T cells with persistent or new T cell receptor (TCR) signalling, respectively. In this favourable therapeutic context, we reveal increased richness of the TCR repertoire and the emergence of numerous and large TCR clusters that share antigen specificity in response to combination therapy. Collectively, our data point towards promising combination approaches for future clinical testing in HNSCC.

2024-07-04 | GSE267158 | GEO

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