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The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to govern anti-tumor immunity

ABSTRACT: The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to govern anti-tumor immunity

PROVIDER: PRJNA1071102 | ENA |

REPOSITORIES: ENA

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The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to govern anti-tumor immunity

Project description:T cell-based cancer immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here, we report that PCIF1, an RNA N6, 2’-O-dimethyladenosine (m6Am) methyltransferase, negatively regulates CD8+ T cell anti-tumor responses. Whole-body or T cell-specific Pcif1 knockout (KO) significantly reduces tumor growth in mice. Single-cell RNA sequencing reveals heightened tumor-infiltrating cytotoxic CD8+ T cells in Pcif1-deficient mice. Mechanistically, proteomic and m6Am-sequencing analyses pinpoint that Pcif1 KO elevates crucial m6Am-modified targets, specifically ferroptosis suppressor genes (Fth1, Slc3a2), and T cell activation gene Cd69, imparting resistance to ferroptosis and enhancing CD8+ T cell activation. Of note, Pcif1-deficient mice with tumors exhibit enhanced responses to anti-PD-1 immunotherapy, and Pcif1 KO CAR T cells demonstrate improved tumor control. Clinically, cancer patients with low PCIF1 expression in T cells exhibit enhanced responses to immunotherapies. These findings suggest that PCIF1 suppresses CD8+ T cell activation and targeting PCIF1 as a promising strategy to boost anti-tumor immunity.

2024-11-14 | GSE254597 | GEO

The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to govern anti-tumor immunity

Project description:Pcif1 KO mice can significantly inhibit tumor growth. We attempted to explore the changes in tumor immune microenvironment of tumor-bearing mice after Pcif1 KO by single-cell sequencing.

2024-11-14 | GSE254353 | GEO

Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.

2024-09-19 | GSE268205 | GEO

Intrahepatic microbes govern liver immunity by programming NKT cells

Project description:Intrahepatic microbes govern liver immunity by programming NKT cells

| PRJNA679769 | ENA

m6A-seq data analysis of control and PCIF1 knockdown transcriptome

Project description:Purpose: To identify the in vivo RNA targets of PCIF1, we performed meRIP experiments for PCIF1 KD and control cells using an anti-m6A antibody. We envisioned that the cap-specific PCIF1 should selectively alter the m6Am modification at the 5-terminal region of transcripts. Indeed, we observed a reduction of modification peaks at the 5’-end but not the 3’-UTR regions of mRNA upon PCIF1 KD.

2018-12-20 | GSE120229 | GEO

Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance [RNA-Seq]

2024-09-19 | GSE268293 | GEO

Effect of PCIF1 knockdown on gene exppression in HeLa S3 cells

Project description:We previously identified PCIF1 (Phosphorylated CTD Interacting Factor 1) as a novel phosphorylated C-terminal domain (CTD) of RNA polymerase II. We also recently identified PCIF1 as a new cap-specific adenine N6 methyltransferase (CAPAM) responsible for creating N6, 2’-O-dimethyladenosine (m6Am) at the 5’-end of mRNAs. However, it remains unclear how PCIF1 regulates gene expression. To identify genes whose expression levels are affected by PCIF1 knockdown in human cultured cells, we performed gene expression profiling by microarray analysis.

2023-09-30 | GSE156768 | GEO

Nuclear localization of fly Pcif1 is required for gene regulation and fertility

Project description:Here we show that Pcif1 mutant flies display a reduced fertility which is particularly marked in females. Deep sequencing analysis of Pcif1 mutant ovaries revealed transcriptome changes with a notable increase in expression of genes belonging to the mitochondrial ATP synthetase complex.

2023-03-09 | GSE218059 | GEO

The mammalian cap-specific m6Am RNA methyltransferase PCIF1 regulates transcript levels in mouse tissues

Project description:The 5' end of eukaryotic mRNAs is protected by the m7G-cap structure. The transcription start site nucleotide is ribose methylated (Nm) in many eukaryotes, while an adenosine at this position is further methylated at the N6 position (m6A) by the mammalian Phosphorylated CTD-interacting Factor 1 (PCIF1) to generate m6Am. Here we show that while loss of cap-specific m6Am in mice does not affect viability or fertility, the Pcif1 mutants display reduced body-weight. Transcriptome analyses of mutant mouse tissues support a role for the cap-specific m6Am modification in stabilizing transcripts. In contrast, the Drosophila Pcif1 is catalytically-dead, but like its mammalian counterpart it retains the ability to associate with the Ser5-phosphorylated CTD of RNA pol II. Finally, we show that the Trypanosoma Pcif1 is an m6Am methylase that contributes to the N6,N6,2?-O-trimethyladenosine (m62Am) in the hypermethylated cap4 structure of Trypanosomatids. Thus, PCIF1 has evolved to function in catalytic and non-catalytic roles.

2020-08-28 | GSE151229 | GEO

Pro-Seq of MEL624 control and PCIF1 KO cells

Project description:We analyzed human melanoma cells by PRO-Seq in order to determine the effect of PCIF1 KO in Pol II dynamics

2019-06-01 | GSE122802 | GEO