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Proteome of SUDIPG, SF7761 and primary non diseased brain samples

ABSTRACT: DIPG is a paediatric brainstem glioma with no cure. Cellular immunotherapy approaches require specific targeting of unique and tumour specific cell surface antigens, however, there is a paucity of known targets for DIPG. In this study we have used a proteomics approach to interrogate an array of patient derived DIPG cell lines to identify potential immunotherapy targets

INSTRUMENT(S): maXis

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Cell Culture

DISEASE(S): Brain Cancer

SUBMITTER: Kirti Pandey

LAB HEAD: Anthony Wayne Purcell

PROVIDER: PXD038372 | Pride | 2023-10-24

REPOSITORIES: Pride

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			Action	DRS
	Proteomics_file.zip	Other
	peptides.txt	Txt
	proteinGroups.txt	Txt

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Publications

A combined immunopeptidomics, proteomics, and cell surface proteomics approach to identify immunotherapy targets for diffuse intrinsic pontine glioma.

Pandey Kirti K Wang Stacie S SS Mifsud Nicole A NA Faridi Pouya P Davenport Alexander J AJ Webb Andrew I AI Sandow Jarrod J JJ Ayala Rochelle R Monje Michelle M Cross Ryan S RS Ramarathinam Sri H SH Jenkins Misty R MR Purcell Anthony W AW

Frontiers in oncology 20230811

<h4>Introduction</h4>Diffuse intrinsic pontine glioma (DIPG), recently reclassified as a subtype of diffuse midline glioma, is a highly aggressive brainstem tumor affecting children and young adults, with no cure and a median survival of only 9 months. Conventional treatments are ineffective, highlighting the need for alternative therapeutic strategies such as cellular immunotherapy. However, identifying unique and tumor-specific cell surface antigens to target with chimeric antigen receptor (CA ...[more]

PMID: 37637064

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The immunopeptidome and proteome of DIPG

Project description:DIPG is a devastating paediatric and young adult brainstem tumour with no cure and a median overall survival of 9 months. Cellular immunotherapy approaches require specific targeting of unique and tumour specific cell surface antigens, however, there is a paucity of known targets for DIPG. Here we used a proteomics platform approach to interrogate an array of patient derived DIPG cell lines to facilitate a multi-omics based approach to identify cell surface protein candidates enriched or unique to DIPG.

2023-09-25 | PXD038271 | Pride

Extracellular matrix educates a tumor macrophage phenotype found in ovarian cancer metastasis

Project description:Recent studies have shown the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and immunotherapy response. A question that remains is whether the ECM is directly educating the immune phenotypes seen in cancer. We identified a tumor-associated macrophage (TAM) population correlated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether ECM was capable of generating the TAM phenotype seen, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissues. ECM educated macrophages have a tissue remodeling and immunoregulatory phenotype, inducing altered T cell function. We conclude that the tumor ECM is directly educating this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

2023-04-11 | PXD036940 | Pride

Non-inflammatory tumor microenvironment of Diffuse Intrinsic Pontine Glioma (DIPG)

Project description:Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9-11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult glioblastomas (GBM). Thus, we directly compared inflammatory characteristics of DIPG and adult GBM. We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b+ macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments.

2018-08-23 | GSE115397 | GEO

Hotspot DNMT3A and IDH1/2 Mutations in Acute Myeloid Leukemia and Their Relevance as Targets for Immunotherapy

Project description:DNA methyltransferase 3A (DNMT3A) and isocitrate dehydrogenase 1 & 2 (IDH1/2) are genes involved in epigenetic regulation, each mutated in 7-23% of acute myeloid leukemia (AML). Here, we investigated whether hotspot mutations in these genes encode neoantigens that can be targeted by immunotherapy. Five EBV-B cell lines expressing common HLA class I alleles were transduced with a minigene construct containing mutations that often occur in DNMT3A or IDH1/2. Peptides eluted from HLA class I alleles on these EBV-B cell lines were analyzed by tandem mass spec-trometry. We identified an HLA-A*01:01-binding DNMT3AR882H peptide and HLA-B*07:02-binding IDH2R140Q peptide, for which we searched for specific T cells in healthy individuals using pep-tide-HLA tetramers. Various T-cell clones were isolated showing specific reactivity against cell lines transduced with full-length DNMT3AR882H or IDH2R140Q genes, while cell lines transduced with wildtype genes were not recognized. One T-cell clone for DNMT3AR882H also reacted against patient AML cells with the mutation, while AML cells without the mutation were not recognized, thereby validating surface presentation of a DNMT3AR882H neoantigen that can potentially be targeted on HLA-A*01:01 positive AML by immunotherapy.

2024-06-23 | PXD050560 | Pride

Ischemic stroke mice brain LC-MSMS

Project description:This study determined the influence of myeloid cell Trim59 deficiency on experimental stroke outcomes and the cerebral proteomic profile using myeloid cell Trim59 conditional knockout (Trim59-cKO) mice, the middle cerebral artery occlusion/reperfusion ischemic model, and a label-free quantitative proteomic profiling technique.

2024-08-02 | PXD049258 | Pride

A complete peptidome workflow for neoantigen identification and validation by mass spectrometry-based immunopeptidomics

Project description:We proposed a complete workflow for neoantigen identification and validation based solely on MS immunopeptidomics.We first developed a new Neo DiscoveryTM immunopeptidome enrichment Kit, which can be used for HLA peptide purification from a small amount of biopsied tissue as low as 18mg. To achieve high sensitivity with such a low amount of sample, we leveraged the power of deep learning and a massive amount of MS-based immunopeptidomics data to build DeepNovo-HLA, a de novo sequencing model specialized for HLA peptides. We also developed DeepImmu, a personalized model for immunogenicity prediction based on the central tolerance of T cells, i.e. the positive and negative selection of T cells in an individual patient.

2024-05-04 | PXD046370 | Pride

Malonylation of Acetyl-CoA Carboxylase 1 Promotes Hepatic Steatosis and Is Attenuated by Ketogenic Diet in NAFLD

Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.

2023-07-21 | PXD040481 | Pride

µPhos: a scalable and sensitive platform for functional phosphoproteomics

Project description:Mass spectrometry has revolutionized cell signaling research by vastly simplifying the analysis of many thousands of phosphorylation sites in the human proteome. Defining the cellular response to perturbations in space and time is crucial for further illuminating functionality of the phosphoproteome. Here we describe µPhos (‘microPhos’), an accessible phosphoproteomics platform that permits phosphopeptide enrichment from 96-well cell culture experiments in <8 hours total processing time. By minimizing transfer steps and reducing liquid volumes to <100 µL, we demonstrate increased sensitivity, >90% selectivity, and excellent quantitative reproducibility. Employing highly sensitive trapped ion mobility mass spectrometry, we quantify >30,000 unique phosphopeptides in a human cancer cell line using 20 µg starting material, and confidently localize >10,000 phosphsites from 1 µg. This depth covers key signaling pathways, rendering sample-limited applications and perturbation experiments with hundreds of samples viable as we demonstrate by profiling the time-resolved response of leukemia cells to tyrosine kinase inhibitors.

2024-05-27 | PXD043370 | Pride

Identification of potential interactors of NKS1 and QUA1

Project description:Adjacent plant cells are connected by specialized cell wall regions, called middle lamellae, which influence critical agricultural characteristics, including fruit ripening and organ abscission. Middle lamellae are enriched in pectin polysaccharides, specifically homogalacturonan (HG). Pectins are made in the Golgi apparatus by the coordinated action of transporters and enzymes. Here, in this project, we identify a plant-specific Arabidopsis DUF1068 protein, called NKS1/ELMO4, that is required for middle lamellae integrity and cell adhesion. We did an immunoprecipitation-mass spectrometry (IP-MS) analysis to identify potential interactors of NKS1. And we also performed an IP-MS analysis of QUA1, which is one of the interactors of NKS1.

2024-03-20 | PXD047727 | Pride

Intra-patient clonal diversity in HLA class I peptide ligand presentation

Project description:Tumor heterogeneity results from clonal diversity and evolutionary selection, and is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug resistant cells, and tumor-specific HLA peptide ligands on the cell surface are promising leads to invoke such targeted anti-tumor responses. In this work, we investigate the variability in HLA class I peptide presentation between tumor cells of the same patient, as differential ligand presentation could impact the efficacy of immunological interventions. By organoid amplification, we modeled single-cell level heterogeneity in a MSI- colorectal cancer patient, and directly correlated clonal tumor proteomes with the respective ligandomes. With deep comparative proteome profiling and sensitive detection of >7000 peptide ligands from each tumor organoid line, we found tumor-surface peptide presentation to be largely uncoupled from the steady-state protein abundance. Within the small minority of tumor-specific ligands (~3%), source proteins needed for DNA damage sensing and repair, and tumor suppression were prominently featured, leading us to speculate that such peptides may be consistently presented, as degradative byproducts of intended silencing. While clone-specific differences in peptide presentation were observed, inter-clone variability was also highly prevalent (15-25%). Collectively, these illustrate the heterogeneous peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.

2020-10-26 | PXD016582 | Pride