In:
Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-2-10)
Abstract:
Pancreatic cancer (PACA), which is characterized by an immunosuppressive nature, remains one of the deadliest malignancies worldwide. Aberrant DNA methylation (DNAm) reportedly influences tumor immune microenvironment. Here, we evaluated the role of DNA methylation driven genes (MDGs) in PACA through integrative analyses of epigenomic, transcriptomic, genomic and clinicopathological data obtained from TCGA, ICGC, ArrayExpress and GEO databases. Thereafter, we established a four-MDG signature, comprising GPRC5A, SOWAHC, S100A14, and ARNTL2. High signature risk-scores were associated with poor histologic grades and late TNM stages. Survival analyses showed the signature had a significant predictive effect on OS. WGCNA revealed that the signature may be associated with immune system, while high risk-scores might reflect immune dysregulation. Furthermore, GSEA and GSVA revealed significant enrichment of p53 pathway and mismatch repair pathways in high risk-score subgroups. Immune infiltration analysis showed that CD8+ T cells were more abundant in low score subgroups, while M0 macrophages exhibited an opposite trend. Moreover, negative regulatory genes of cancer-immunity cycle (CIC) illustrated that immunosuppressors TGFB1, VEGFA, and CD274 (PDL1) were all positively correlated with risk-scores. Furthermore, the four signature genes were negatively correlated with CD8+ lymphocytes, but positively associated with myeloid derived suppressor cells (MDSC). Conversely, specimens with high risk-scores exhibited heavier tumor mutation burdens (TMB) and might show better responses to some chemotherapy and targeted drugs, which would benefit stratification of PACA patients. On the other hand, we investigated the corresponding proteins of the four MDGs using paraffin-embedded PACA samples collected from patients who underwent radical surgery in our center and found that all these four proteins were elevated in cancerous tissues and might serve as prognostic markers for PACA patients, high expression levels indicated poor prognosis. In conclusion, we successfully established a four-MDG-based prognostic signature for PACA patients. We envisage that this signature will help in evaluation of intratumoral immune texture and enable identification of novel stratification biomarkers for precision therapies.
Type of Medium:
Online Resource
ISSN:
1664-3224
DOI:
10.3389/fimmu.2022.803962
DOI:
10.3389/fimmu.2022.803962.s001
DOI:
10.3389/fimmu.2022.803962.s002
DOI:
10.3389/fimmu.2022.803962.s003
DOI:
10.3389/fimmu.2022.803962.s004
DOI:
10.3389/fimmu.2022.803962.s005
DOI:
10.3389/fimmu.2022.803962.s006
DOI:
10.3389/fimmu.2022.803962.s007
DOI:
10.3389/fimmu.2022.803962.s008
DOI:
10.3389/fimmu.2022.803962.s009
DOI:
10.3389/fimmu.2022.803962.s010
DOI:
10.3389/fimmu.2022.803962.s011
DOI:
10.3389/fimmu.2022.803962.s012
DOI:
10.3389/fimmu.2022.803962.s013
DOI:
10.3389/fimmu.2022.803962.s014
DOI:
10.3389/fimmu.2022.803962.s015
DOI:
10.3389/fimmu.2022.803962.s016
DOI:
10.3389/fimmu.2022.803962.s017
DOI:
10.3389/fimmu.2022.803962.s018
DOI:
10.3389/fimmu.2022.803962.s019
DOI:
10.3389/fimmu.2022.803962.s020
DOI:
10.3389/fimmu.2022.803962.s021
DOI:
10.3389/fimmu.2022.803962.s022
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2022
detail.hit.zdb_id:
2606827-8
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