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Prognostic value of PDL1 expression in pancreatic cancer.

ABSTRACT: Pancreatic cancer is one of the most aggressive human cancers. PD1/PDL1-inhibitors recently showed promising results in different cancers with correlation between PDL1 tumor expression and responses. Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in pancreatic cancer. In this retrospective study, we analyzed PDL1 mRNA expression in 453 clinical pancreatic cancer samples profiled using DNA microarrays and RNASeq. Compared to normal pancreatic samples, PDL1 expression was upregulated in 19% of cancer samples. Upregulation was not associated with clinicopathological features such as patients' age and sex, pathological type, tumor size, lymph node status, and grade, but was associated with shorter disease-free survival and overall survival in multivariate analyses. Analysis of correlations with biological parameters showed that PDL1 upregulation was associated with some degree of lymphocyte infiltration and signs of anti-tumor T-cell response, but to a lesser extent than what has been reported in breast cancer and GIST. PDL1-up pancreatic cancers displayed profiles of lymphocyte exhaustion, were more enriched in inhibitory molecules and pro-tumor populations (Tregs with upregulation of FOXP3 and IL10, myeloid-derived suppressor cells with upregulation of CD33 and S100A8/A9), and demonstrated a down-modulation of most MHC class I members (HLA-A/B/C, HLA-E/F/G) suggestive of a defect in antigen processing and presentation. In conclusion, our results suggest that PDL1 expression might refine the prediction of metastatic relapse in operated pancreatic cancer, and that PD1/PDL1 inhibitors might reactivate inhibited T-cells to increase the anti-tumor immune response in PDL1-upregulated tumors.

SUBMITTER: Birnbaum DJ

PROVIDER: S-EPMC5342072 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Prognostic value of PDL1 expression in pancreatic cancer.

Birnbaum David J DJ Finetti Pascal P Lopresti Alexia A Gilabert Marine M Poizat Flora F Turrini Olivier O Raoul Jean-Luc JL Delpero Jean-Robert JR Moutardier Vincent V Birnbaum Daniel D Mamessier Emilie E Bertucci François F

Oncotarget 20161101 44

Pancreatic cancer is one of the most aggressive human cancers. PD1/PDL1-inhibitors recently showed promising results in different cancers with correlation between PDL1 tumor expression and responses. Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in pancreatic cancer. In this retrospective study, we analyzed PDL1 mRNA expression in 453 clinical pancreatic cancer samples profiled using DNA microarrays and RNASeq. Compared to normal pancreatic samples, PDL1 ...[more]

PMID: 27589570

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Project description:Background: The histone lysine demethylase KDM5 family is an important epigenetic state-modifying enzyme family. Increasing evidence supports that epigenetic abnormalities in the KDM5 family are related to multiple cancers in humans. However, the role of the KDM5 family in pancreatic cancer is not clear, and related research is very scarce. Methods: R software, Kaplan-Meier Plotter, cBioPortal, TIMER, LinkedOmics, STRING, Metascape, TISIDB, and the GSCA Lite online tool were utilized for bioinformatics analysis. Results: KDM5A/B/C was significantly overexpressed in many kinds of tumor tissues, including pancreatic adenocarcinoma (PAAD), while the expression of KDM5D was significantly downregulated. The high expression of KDM5A/B/C was related to poor clinical features, such as worse treatment efficacy, higher tumor grade, and more advanced clinical stage. Patients with a family history of breast cancer and melanoma, history of drinking or history chronic pancreatitis were more likely to have KDM5A/B/C gene abnormalities, which were related to a variety of adverse clinical features. The results of gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway analyses of the KDM5 family and its 800 co-expressed genes showed that many gene terms related to cell proliferation, migration and many carcinogenic pathways. Notably, we found that the expression level of KDM5A/B/C was positively correlated with the expression of multiple key driver genes such as KRAS, BRCA1, and BRCA2 etc. In addition, PPI network analysis showed KDM5 family proteins have strong interactions with histone deacetylase family 1 (HDAC1), which could modify the lysines of histone H3, and co-act on many pathways, including the "longevity-regulating pathway" and "Notch signaling pathway". Moreover, the upregulation of KDM5A/B/C expression was associated with an increase in the infiltration of B cells, CD8+ T cells and other infiltrating immune lymphocytes and the expression levels of immune molecules such as NT5E and CD274. Interestingly, the overexpression of KDM5A/C was also corelated with reduced sensitivity of pancreatic cancer cells to many kinds of pancreatic cancer-targeting or chemotherapeutic drugs, including axitinib and gemcitabine. Conclusion: KDM5 family members may be prognostic markers and new therapeutic targets for patients with pancreatic cancer.

Project description:BackgroundIncreasing bodies of evidence reveal that targeting a programmed cell death protein 1 (PD-1) monoclonal antibody is a promising immunotherapy for lung adenocarcinoma. Although PD receptor ligand 1 (PDL1) expression is widely recognized as the most powerful predictive biomarker for anti-PD-1 therapy, its regulatory mechanisms in lung adenocarcinoma remain unclear. Therefore, we conducted this study to explore differentially expressed genes (DEGs) and elucidate the regulatory mechanism of PDL1 in lung adenocarcinoma.MethodsThe GSE99995 data set was obtained from the Gene Expression Omnibus (GEO) database. Patients with and without PDL1 expression were divided into PDL1-positive and PDL1-negative groups, respectively. DEGs were screened using R. The Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed using the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) networks of DEGs was visualized using Cytoscape, and the MNC algorithm was applied to screen hub genes. A survival analysis involving Gene Expression Profiling Interactive Analysis was used to verify the GEO results. Mutation characteristics of the hub genes were further analyzed in a combined study of five datasets in The Cancer Genome Atlas (TCGA) database.ResultsIn total, 869 DEGs were identified, 387 in the PDL1-positive group and 482 in the PDL1-negative group. GO and KEGG analysis results of the PDL1-positive group mainly exhibited enrichment of biological processes and pathways related to cell adhesion and the peroxisome proliferators-activated receptors (PPAR) signaling pathway, whereas biological process and pathways associated with cell division and repair were mainly enriched in the PDL1-negative group. The top 10 hub genes were screened during the PPI network analysis. Notably, survival analysis revealed BRCA1, mainly involved in cell cycle and DNA damage responses, to be a novel prognostic indicator in lung adenocarcinoma. Moreover, the prognosis of patients with different forms of lung adenocarcinoma was associated with differences in mutations and pathways in potential hub genes.ConclusionsPDL1-positive lung adenocarcinoma and PDL1-negative lung adenocarcinoma might be different subtypes of lung adenocarcinoma. The hub genes might play an important role in PDL1 regulatory pathways. Further studies on hub genes are warranted to reveal new mechanisms underlying the regulation of PDL1 expression. These results are crucial for understanding and applying precision immunotherapy for lung adenocarcinoma.

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Prognostic value of PDL1 expression in pancreatic cancer.

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Prognostic value of PDL1 expression in pancreatic cancer.

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