Identification of Therapeutic Targets and Prognostic Biomarkers Among CC Chemokines in the Pancreatic Adenocarcinoma Microenvironment

Abstract

Pancreatic adenocarcinoma (PAAD) as one of the most aggressive and lethal malignant tumors is correlated with increased morbidity and mortality. Tumorigenesis, growth, and metastasis are affected by various cytokines. Among them, CC chemokines can modulate the infiltration of immune cells and recruit cancer-associated immune cells, which play an important role in the inhibition of tumor immunity and affect the clinical outcome of cancer patients. However, the therapeutic potential and prognostic value of CC chemokines in PAAD have not yet been elucidated. To do this, we comprehensively explore and analyze large amounts of data on the basis of ONCOMINE database, GEPIA, LinkedOmics, cBioPortal, GeneMANIA, UALCAN, jvenn, DAVID 6.8, TRRUST, TIMER, and TISIDB. We found the transcriptional levels of CCL5/7/13/15/18/19/20 in PAAD tissues were remarkably increased, whereas the transcriptional level of CCL17 was decreased. CCL20 expression had significantly been correlated with the tumor stage of PAAD patients. High expressions of CCL5, CCL7, CCL13, CCL18, and CCL20 were notably correlated with the prognosis of patients. Moreover, patients with CCL18 and CCL19 alterations showed a poor prognosis in both overall survival (OS) and disease-specific survival (DSS), and patients with CCL5 and CCL15 alterations also presented a poor prognosis in OS. The functions of the aberrantly expressed CC chemokines were mainly correlated with the cytokine-cytokine receptor interaction, chemokine signaling pathway, inflammatory response, and immune response. Our study shows that the key transcription factors for CC chemokines are RELA and NF-κB1. We also discovered significant associations between the expression levels of CC chemokines and six infiltrating immune cells including CD8+ T cells, CD4+ T cells, B cells, macrophages, neutrophils, and dendritic cells. Taken together, our study indicated the interaction between CC chemokines and PAAD and clarified the value of CC chemokines as potential therapeutic targets as well as prognostic markers for PAAD.