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A metabolomic and proteomic study to elucidate the molecular mechanisms of immunotherapy resistance in patients with oesophageal squamous cell carcinoma

ABSTRACT: Systemic chemotherapy, the standard first-line treatment option for patients with advanced oesophageal squamous cell carcinoma (OSCC), results in a median survival of approximately 1 year. Immune checkpoint inhibitors are a breakthrough oncology treatment option; however, most patients with advanced OSCC develop primary and acquired resistance to PD-1 monoclonal antibody, severely affecting their prognosis. Therefore, there is an urgent need to investigate the molecular mechanism underlying resistance to treatment. This study aimed to explore the mechanism of resistance to PD-1 monoclonal antibody. We collected plasma samples from patients with OSCC treated with immunotherapy, who achieved pathological response/partial response (CR/PR) or stable disease/progressive disease (SD/PD) after one treatment cycle. TM widely targeted metabolomics, widely targeted lipidomics, and DIA proteomics assays were performed. Differential metabolites were screened based on fold change (FC) ≥ 1.5 or ≤ 0.67 and a VIP ≥ 1; differential proteins were screened based on FC > 1.5 or < 0.67 and a p-value < 0.05. The identified metabolites were annotated and mapped using the KEGG pathway databases The differential proteins were annotated to the Gene Ontology and KEGG pathway databases. A correlation network diagram was drawn using differential expressed proteins and metabolites with (Pearson correlation coefficient) r > 0.80 and p-value <0.05. We finally screened 197 and 113 differential metabolites and proteins, respectively, in patients with CR/PR and SD/PD groups. The KEGG enrichment analysis revealed that all of these were enriched in cholesterol metabolism and in the NF-κB and phospholipase D signalling pathways. Our study is the first to demonstrate that PD-1 inhibitor resistance may be attributed to cholesterol metabolism or NF-κB and phospholipase D signalling pathway activation. This finding suggests that targeting these signalling pathways may be a promising novel therapeutic approach in OSCC which may improve prognosis in patients undergoing immunotherapy.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lijuan Gao

PROVIDER: PXD039045 | iProX | Thu Dec 22 00:00:00 GMT 2022

REPOSITORIES: iProX

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A metabolomic and proteomic study to elucidate the molecular mechanisms of immunotherapy resistance in patients with oesophageal squamous cell carcinoma.

Gao Lijuan L Chen Yongshun Y

Biomedical reports 20230406 5

Systemic chemotherapy, the standard first-line treatment option for patients with advanced oesophageal squamous cell carcinoma (OSCC), results in a median survival of ~1 year. Immune checkpoint inhibitors are a breakthrough oncology treatment option; however, most patients with advanced OSCC develop primary and acquired resistance to programmed death receptor-1 (PD-1) monoclonal antibody, severely affecting their prognosis. Therefore, there is an urgent need to investigate the molecular mechanis ...[more]

PMID: 37089578

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Project description:OBJECTIVE: To investigate the differentially expressed genes related to the chemosensitivity of laryngeal squamous cell carcinoma ï¼LSCCï¼by microarrays arrays. METHODS: 1. A total number of 11 patients who underwent induction chemotherapy for primary hypopharyngeal squamous cell carcinoma (7 patients are sensitive to chemotherapy ,and others are not) were recruited for microarray and miRNA array gene expression analysis 2. Bioinformatics analysis of differentially expressed genes screened by microarrays : The differential gene cluster analysis was applied in biological processes, cellular components and molecular functions by GO database; The differential gene enrichment analysis was applied in signaling pathways by KEGG database, and the differentially expressed and biologically meaningful core genes would be screened. RESULTS: 1. Analyzed by microarrays, there were 1554 genes significantly related to the sensitivity to chemotherapy; Among these 1554genes, 777 showed a higher expression in the tissue from patients who are sensitive to chemotherapy , while 785 presented the contrasting pattern. CONCLUSIONS: The research revealed a gene expression signature of chemosensitivity in laryngeal squamous cell carcinoma by microarrays arrays. The result will contribute to the understanding of the molecular basis of laryngeal squamous cell carcinoma and help to improve diagnosis and treatment. 1. A total number of 11 patients who underwent induction chemotherapy for primary hypopharyngeal squamous cell carcinoma (7 patients are sensitive to chemotherapy ,and others are not) were recruited for microarray and miRNA array gene expression analysis 2. Bioinformatics analysis of differentially expressed genes screened by microarrays : The differential gene cluster analysis was applied in biological processes, cellular components and molecular functions by GO database; The differential gene enrichment analysis was applied in signaling pathways by KEGG database, and the differentially expressed and biologically meaningful core genes would be screened.

Project description:With the internationalization of traditional Chinese medicine, the demand for medicinal and edible Codonopsis Radix (CR) is increasing, and its medicinal resources have attracted atten- tion. CR is a famous traditional Chinese medicine with a long pharmaceutical and edible history. Guizhou has abundant CR resources, but in the absence of systematic studies on species identifi- cation and chemical compositions, it has not been fully utilized. The results of plant traits and DNA barcoding molecular identification indicated that Luodang (LD) and Weidang (WD) from Guizhou were Codonopsis tangshen, C. pilosula., respectively. Widely targeted metabolomics analysis revealed that a total of 1116 metabolites from 14 categories, including phenolic acids, lipids, flavonoids, etc., were found in LD, WD, and the three Chinese Pharmacopoeia CR. CRs shared 1054 (94.4%) me- tabolites, with extremely similar metabolite profiles. Affected by Guizhou's particular climate, LD and WD each contained 3 and 10 dominant differential metabolites, respectively, which were pri- marily flavonoids and amino acids. Amino acids, phenolic acids, and organic acids play important roles in the excellent food attributes of them. In CR, 8 dominant differential metabolites were dis- covered for the first time, including isoorientin-7-O-(6′′-feruloyl) glucoside, N-formyl-L-methionine, and cyclo (Phe-Glu), etc. Network pharmacology analyses showed that LD dominant differential metabolites were closely related to anti-tumor, cardiovascular disease improvement, nervous system protection, and metabolic disease treatment, whereas WD was closely related to nervous system protection and cardiovascular disease improvement. In conclu- sion, LD and WD can be used and promoted medicinally as CR and have potential value for new drug development. This work enriched the database of CR compounds and provided a reference for quality control, resource development, and new drug development of CR

Dataset Information

A metabolomic and proteomic study to elucidate the molecular mechanisms of immunotherapy resistance in patients with oesophageal squamous cell carcinoma

Publications

A metabolomic and proteomic study to elucidate the molecular mechanisms of immunotherapy resistance in patients with oesophageal squamous cell carcinoma.

Similar Datasets

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