Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

M1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating PD-L1 expression

ABSTRACT: RNA N1-methyladenosine methylation (m1A) modification is critical in regulating mRNA translation and thus protein synthesis, but the role of m1A modification in the occurrence, progression, and immunotherapy of head and neck squamous cell cancer (HNSCC) remains largely unknown. In Tgfbr1/Pten 2cKO mice, we found that the spontaneous neoplastic transformation of oral mucosa is accompanied by elevated levels of m1A modification. Analysis of m1A-associated genes identified TRMT61A as the key m1A writer associated with cancer progression, and poor prognosis. Mechanically, TRMT61A-induced tRNA-m1A modification promotes MYC protein synthesis and subsequent programmed death-ligand 1 (PD-L1) expression. In Tgfbr1/Pten 2cKO mice, RNA-m1A modification levels are also elevated in tumors that developed resistance to oncolytic herpes simplex virus (oHSV) treatment. Therapeutic inhibition of m1A modification sustains oncolytic virus-induced antitumor immunity and reduces tumor growth, providing a promising strategy for alleviating resistance to oHSV therapy. These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing the expression of PD-L1. Our results provide a mutually reinforcing strategy for clinical combination immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247024 | GEO | 2024/03/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells

Project description:Activation of CD8+ T cells necessitates rapid metabolic reprogramming to fulfill the substantial biosynthetic demands of their effector functions. However, the post-transcriptional mechanisms underpinning this process remain obscure. The tRNA N1-methyladenine (m1A) modification, which plays a role in maintaining tRNA stability and modulating protein translation, has an undefined physiological function in CD8+ T cells, particularly in antitumor responses. Here, we demonstrate that the tRNA m1A 'writer' gene Trmt61a enhances the tumor-killing capacity of CD8+ T cells by regulating cholesterol biosynthesis. We find that Trmt61a expression in CD8+ T cells is upregulated upon activation and correlates positively with T cell-mediated cytotoxicity within the tumor microenvironment of colorectal cancer (CRC) patients. Deletion of Trmt61a in CD8+ T cells leads to a compromised tumor-killing function in both in vivo and in vitro assays, which is dependent on the m1A catalytic activity of TRMT61A. Mechanistically, tRNA m1A promotes antitumor immunity in CD8+ T cells by enhancing the translation of ATP citrate lyase (ACLY), a key enzyme for cholesterol biosynthesis. Supplementation with cholesterol can rescue the impaired tumor-killing function and proliferation of TRMT61A-deficient CD8+ T cells. Our findings underscore the significance of tRNA m1A modification as a regulatory checkpoint in cholesterol metabolism in CD8+ T cells, suggesting potential novel strategies for cancer immunotherapy.

2025-01-07 | GSE275602 | GEO

RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal cancer [Ribo-Seq]

Project description:The role of N1-methyladenosine (m1A) in cancer remains poorly understood. Here we investigate the functional importance of RNA m1A methyltransferase TRMT61A in colorectal cancer (CRC) and assess its potential as a therapeutic target. Our findings demonstrate consistent elevation of TRMT61A expression and RNA m1A levels in primary CRC tissues, which correlate significantly with poor patient survival. Through CRISPR/Cas9 screenings, TRMT61A is the most essential gene among m1A regulators. We further elucidate that TRMT61A facilitates CRC tumorigenesis and progression by enhancing the stability of mRNA of crucial targets, including ONECUT2, thereby activating the MAPK/ERK signaling pathway in an m1A-dependent manner. Of note, we show promising anti-CRC effects by inhibiting TRMT61A using nanoparticleencapsulated siTRMT61A or our identified small molecule compound, PGG. Collectively, our study uncovers the essential role of TRMT61A-m1A in CRC by activating the ONECUT2-MAPK/ERK pathway. Targeting TRMT61A holds promise as a therapeutic approach for treating CRC.

2025-02-01 | GSE274079 | GEO

RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal cancer [MeRIP-Seq]

2025-02-01 | GSE274076 | GEO

RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal cancer II

2025-02-01 | GSE274028 | GEO

RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal cancer I

2025-02-01 | GSE274027 | GEO

Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

Project description:Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

2024-07-07 | GSE267312 | GEO

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway

Project description:Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell‑intrinsic functions in immune and cancer cells. In line with these studies, here we show that PD-L1 potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cells resulted in enhanced infection with oncolytic viruses in cancer cells in vitro and in vivo. PD-L1 expression marks tumor explants from cancer patients that are best infected by oncolytic viruses. Agonistic antibodies targeting PD-L1 further reduced type I IFN responses and enhanced oncolytic virus infection. Mechanistically, PD-L1 suppressed type I interferon by promoting Warburg metabolism, characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD‑L1‑expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

2023-06-28 | GSE210884 | GEO

Transcription profiling of human MPNST cancer cells infected with G207 an oncolytic HSV

Project description:We used microarrays to identify genes regulated during oncolytic HSV infection. Oncolytic herpes simplex viruses (oHSV) are promising anticancer therapeutics. We sought to identify alterations in gene expression during oHSV infection of human cancer cells. Human malignant peripheral nerve sheath tumor (MPNST) cells were infected with G207, an ICP34.5-deleted oHSV previously evaluated in clinical trials. G207-infected cells demonstrated massive degradation of cellular mRNAs, while a subset were upregulated. A gene signature of 21 oHSV-induced genes contained 7 genes known to be HSV-induced. Go ontology classification revealed that a majority of upregulated genes are involved in Jak/STAT signaling, transcriptional regulation, nucleic acid metabolism, protein synthesis and apoptosis. Ingenuity-defined functional networks highlighted nodes for AP-1 subunits and interferon signaling via STAT1, SOCS1, SOCS3 and RANTES. Upregulation of SOCS1 correlated with sensitivity of MPNST lines to G207 and depletion of SOCS1 reduced virus replication >1-log. The transcriptome of oHSV-induced genes may predict oncolytic efficacy and provides rationale for next generation oncolytics. Experiment Overall Design: 5 human MPNST cancer cell lines were infected with G207 or mock infected for 6 hours followed by RNA extraction and hybridization on Affymetrix microarrays.

2008-06-16 | E-GEOD-8717 | biostudies-arrayexpress

Chemical manipulation of m1A mediates its detection in human tRNA

Project description:N1-methyl adenosine (m1A) is a wide-spread RNA modification present in tRNA, rRNA and mRNA. m1A modification sites in tRNAs are evolutionary conserved and its formation on tRNA is catalyzed by methyltransferase TRMT61A and TRMT6 complex. m1A promotes translation initiation and elongation. Due to its positive charge under physiological conditions, m1A can notably modulate RNA structure. It also blocks Watson-Crick base pairing and causes mutation and truncation during reverse transcription. Several misincorporation-based high throughput sequencing methods have been developed to sequence m1A. In this study, we introduce a reduction-based m1A sequencing (red-m1A-seq). We report that NaBH4 reduction of m1A can improve the mutation and readthrough rates using commercially available RT enzymes to give better positive signature, while alkaline-catalyzed Dimroth rearrangement can efficiently convert m1A to m6A to provide good controls, allowing the detection of m1A with higher sensitivity and accuracy. We applied red‑m1A-seq to sequence human small RNA and we not only detected all the previously reported tRNA m1A sites, but also new m1A sites in mt-tRNAAsn-ATT and 5.8S rRNA.

2024-04-24 | GSE253657 | GEO

N1-methyladenosine methylations in tRNA drive liver tumorigenesis by PPARδ-mediated cholesterol synthesis

Project description:Increased protein translation plays a critical role in cancer development and treatment1,2. However, the molecular mechanism that is involved in this process remains poorly understood. N1-methyladenosine (m1A) methylation in RNA accounts for regulating mRNA translation in a post-transcriptional manner3,4. Here we show that m1A methylation levels are remarkably elevated in hepatocellular carcinoma (HCC) patient tumor tissues, especially in patients with microscopic vascular invasion (MVI). Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. Consistently, TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumors and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylations are required for self-renewal of liver CSCs and tumorigenesis. Mechanistically, TRMT6/TRMT61A-dependent m1A in tRNA boost PPARδ expression, which triggers cholesterol synthesis to activate Hedgehog signaling, driving self-renewal of liver CSCs and tumorigenesis. For potential therapeutic benefit, we further identify a specific inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer with high m1A methylations. Our findings provide novel insights into the function and molecular mechanism of m1A modifications underlying liver tumorigenesis and drug target, which will serve as a new biomarker for HCC and pave a new way to develop more effective therapeutic strategies for HCC patients.

2021-03-01 | GSE147840 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data