Bioinformatics-based Investigation to Unveiling The miRNA-Immunity Axis in The Tumor Microenvironment of Pancreatic Cancer.

BACKGROUND

In this Bioinformatics study, we took in account the cell types variation of tumor microenvironment (TME) in Pancreatic Ductal Adenocarcinoma (PDAC), with a particular attention to miRNAs dysregulated pathways influencing immune responses, and especially memory CD4+ T cells.

METHODS

For cell types and differentially expressed genes in memory CD4+ T cells, scRNA-seq was conducted on PDAC and non-tumoral pancreas samples. Putative miRNA targeting sequences on downregulated genes were investigated by three prediction databases, MiRWalk, TargetScan, and miRDB, and compared to GSE207345's differential expression with creation of Affymetrix Multispecies miRNA-4 Array. The miRNA-mRNA interaction network was established in Cytoscape.

RESULTS

Memory CD4+ T cells were significantly enriched in PDAC TME. At the same time, we observed genotype-specific repression of major immune and metabolic genes in these cells. Some miRNAs were significantly overexpressed in PDAC, and hsa-miR-1207-5p, hsa-miR-6805-5p, and hsa-miR-149-3p might target many immune-related or pancreatic enzyme-associated genes. Of these, a core of CLPS, NR4A2, and SOCS3 was most frequently targeted, which likely indicated the importance of these genes in immune evasion.

CONCLUSIONS

While memory CD4+ T cells exist within the PDAC TME, their activity is suppressed by miRNA-associated gene dysregulation. These data suggest candidate therapeutic approaches in which targeting of miRNAs could be used to normalize immune cells and promote anti-tumor immunity.