Metabolomics data for Figure 1D-1F. Schofield et al, Cell Reports, "Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides"
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ABSTRACT:
INSTRUMENT(S): Orbitrap ID-X
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Zach Schafer
PROVIDER: MSV000094226 | MassIVE | Sun Mar 03 14:31:00 GMT 2024
SECONDARY ACCESSION(S): PXD050289
REPOSITORIES: MassIVE
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Project description:Metabolomics raw LCMS files for Figure 1D-1F. Schofield et al, Cell Reports, "Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides".
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Project description:The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only about 1% Hodgkin and Reed/Sternberg (HRS) tumor cells. T cells are usually the largest population of cells in the cHL microenvironment, encompassing T helper (Th) cells, regulatory T (Treg) cells and cytotoxic T cells. Th and Treg cells presumably provide essential survival signals for HRS cells. Treg cells are also involved in rescuing HRS cells from anti-tumor immune responses. An understanding of the immune evasion strategies of HRS cells is not only highly relevant for a characterization of the pathophysiology of cHL, but also clinically, given the current treatment approaches targeting checkpoint inhibitors. Here, we characterized the cHL-specific CD4+ T cell infiltrate regarding its role in immune evasion. Global gene expression analysis of CD4+ Th and Treg cells isolated from cHL lymph nodes and reactive tonsils revealed that Treg cell signatures were enriched in CD4+ Th cells of cHL. Hence, HRS cells may induce a Treg differentiation in Th cells, which was supported by in vitro studies with Th cells and cHL cell lines. Furthermore, we found indication for immune-suppressive purinergic signaling and a role of the inhibitory receptor-ligand pairs BTLA-HVEM and CD200R-CD200 in promoting immune evasion. Taken together, this study reveals that the immune evasion strategies in cHL are even more complex and multifaceted than previously recognized.
2017-10-09 | GSE102693 | GEO
Project description:The cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of HIV-1 and initiate the antiviral immune response through cGAS–STING–TBK1–IRF3–type I IFN (IFN-I) signaling cascade. HIV-1 uses several strategies to interfere with the host immune molecules and mediate immune evasion. However, the potential role of HIV-1 proteins in cGAS–STING signaling remains unclear. Here we report that the HIV-1 protein p6 suppresses HIV-1-stimulated expression of IFN-I and promotes the immune evasion. Mechanistically, p6 bound with STING and inhibited the activation of STING and the interaction between STING and TBK1. Moreover, the glutamylation of p6 at Glu6 residue inhibited the interaction between STING and TRIM32 or AMFR, which subsequently suppressed the K27- and K63-linked polyubiquitination of STING at Lys337, therefore inhibited STING activation and type I IFN production, while the mutation of Glu6 residue lost the inhibitory effect. However, CoCl2, an agonist for cytosolic carboxypeptidases (CCPs), counteracted the glutamylation of Glu6 residue of p6 and promoted IFN-I production to block the immune evasion of HIV-1. These findings not only reveal a previously unknown mechanism through which an HIV-1 protein mediate immune evasion, but also provide a new therapeutic drug candidate to treat HIV-1 infection.
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Project description:RNA epigenetics plays crucial roles in physiological and pathological processes. As the most abundant methylation of mRNA, 0.2-0.7% of the total adenosine, m6A is dynamically deposited co-transcriptionally by the methyltransferase complex, reversely removed by demethylases recognized and directly regulated by “reader” proteins. As the first identified m6A ‘reader’ protein, YTHDF2 recognizes and destabilizes m6A modified mRNAs by inducing mRNA decay or degradation in P-body and plays indispensable oncogenic or tumor suppressive roles in multiple malignant contexts by mediating distinct m6A modified mRNAs. Here, we report that YTHDF2 promotes the development of B cell malignancies by facilitating energy supplements and immune evasion. RNA-sequencing (RNA-seq) data reveal that a set of ATP production- and immune response-related genes are consistently and significantly dysregulated upon YTHDF2 knockdown (KD) in both B cell acute lymphoblastic leukemia (B-ALL) patient-derived xenotransplant (PDX) cells (IAH8R) and diffuse large B cell lymphoma (DLBCL) cells (SU-DHL-4). RNA immunoprecipitation sequencing (RIP-seq) of either wildtype or mutant YTHDF2 proteins identify target genes directly bind to YTHDF2 dependent on the RNA binding pockets. Methylation RIP-seq (MeRIP-seq) assays identify either m6A-moidfied genes or m5C-modified mRNAs, which is further confirmed by bisulfite-converted mRNA sequencing (BS-RNA-seq) in malignant B cells. Mechanically, we find that YTHDF2 enhances ATP synthesis by sustaining mRNA stabilities of target genes as an m5C reader protein by interacting with PABPC1, a well-know m5C-modified mRNA stabilizer. Further RNA-seq upon PABPC1 KD and RIP-seq assays for PABPC1 reveal the overlapped genes which are also regulated and bound with YTHDF2 via m5C modification. Strikingly, RNA-seq and m6A-MeRIP-seq data show that YTHDF2 promotes immune evasion by destabilizing CD19 and MHC-II molecules (e.g., HLA-DMA and HLA-DMB) in an m6A-dependent manner. Single cell RNA-seq (scRNA-seq) data further reveal the immune microenvironment and cell proportions in bone marrow of Ythdf2 conditional KO mouse models (Ythdf2fl/fl). Our proof-of-concept study discovers that a YTHDF2 selective inhibitor (e.g. CCI-38) significantly inhibits cell metabolism and immune evasion in malignant B cells (KOPN-8) by RNA-seq. Collectively, our data show that YTHDF2 promotes ATP synthesis and immune evasion and serves as a promising therapeutic target in B cell malignancies.
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Project description:Lysine lactylation is a lactate-induced post-translational modification that links cellular metabolism to biological processes. However, the functional role of this histone mark in cancers remains largely unexplored, partly due to a lack of knowledge about its reader proteins. Here, we identify SMARCA5 as a bona fide effector of H3K18la. Transcriptomics, metabolomics and epigenetics analyses reveal numerous SMARCA5 target genes, enriched for metabolic regulators including HK2, PFKM, and LDHA. We further demonstrate that SMARCA5 facilitates glycolytic activity by recruiting MYC to the promoters of glycolytic genes. Elevated lactate derived from tumor glycolysis similarly increases H3K18la levels in CD8+ T cells and induces inhibitory receptor expression. Consequently, the glycolysis/H3K18la/SMARCA5/MYC positive feedback loop exacerbates tumor metabolism and promotes immune evasion. Pharmacologic inhibitor of LDHA that interrupts this loop attenuates immune evasion and sensitizes cancer cells to immunotherapy. Collectively, we propose SMARCA5 as a bona fide H3K18la reader that promotes tumor progression and immune escape by coupling cellular metabolism to epigenetic regulation.
2025-09-15 | GSE307050 | GEO
Project description:Lysine lactylation is a lactate-induced post-translational modification that links cellular metabolism to biological processes. However, the functional role of this histone mark in cancers remains largely unexplored, partly due to a lack of knowledge about its reader proteins. Here, we identify SMARCA5 as a bona fide effector of H3K18la. Transcriptomics, metabolomics and epigenetics analyses reveal numerous SMARCA5 target genes, enriched for metabolic regulators including HK2, PFKM, and LDHA. We further demonstrate that SMARCA5 facilitates glycolytic activity by recruiting MYC to the promoters of glycolytic genes. Elevated lactate derived from tumor glycolysis similarly increases H3K18la levels in CD8+ T cells and induces inhibitory receptor expression. Consequently, the glycolysis/H3K18la/SMARCA5/MYC positive feedback loop exacerbates tumor metabolism and promotes immune evasion. Pharmacologic inhibitor of LDHA that interrupts this loop attenuates immune evasion and sensitizes cancer cells to immunotherapy. Collectively, we propose SMARCA5 as a bona fide H3K18la reader that promotes tumor progression and immune escape by coupling cellular metabolism to epigenetic regulation.
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Project description:Lactate sensing drives fungal immune evasion
| PRJEB13396 | ENA