179 Association of CX3CR1 and Myeloid-derived Suppressor Cell with Survival of Sepsis Patients and Risk of Acute Respiratory Distress Syndrome

Abstract

Peripheral blood immune micro-environment has been shown to influence survival outcomes in sepsis patients. However, the association of immune micro-environment with clinical outcomes of immune-suppression induced by sepsis remains unclear. Here we performed comprehensive analysis of immune cell infiltration and clinically validated association of CX3CR1 and Myeloid-derived suppressor cell (MDSC) with survival of sepsis patients and risk of acute respiratory distress syndrome (ARDS). This study analyzed discovering cohort including all sepsis patients, which grouped by survival status and ARDS occurrence, from the Gene Expression Omnibus database (GSE10474, GSE32707, GSE66890). Core differential expressed genes (DEGs) and immune cell were selected between groups using LASSO and Random Forest machine learning algorithm. Most survival correlated gene and immune cell were validated in validating cohort (GSE65682) using Kaplan-Meier survival analysis. Since gene and immune cell were selected, patients from discovering cohort were divided into higher and lower group. To further explore underlying mechanism, weighted gene co-expression network analysis (WGCNA) were applied. For functional and pathway enrichment analysis, clusterProfiler R package was used for Gene Ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) analyses. Among 133 sepsis patients from discovering cohort, 110 down-regulated genes and 76 up-regulated genes were identified as DEGs based on the survival status, while 177 down-regulated genes and 89 up-regulated genes were identified as DEGs based on the ARDS risk, respectively. After combining the DEGs screened out via the LASSO and RF algorithms, 13 DEGs between survival status and 16 DEGs between ARDS risk, were selected simultaneously by these two algorithms. The gene of CX3CR1 and immune cell of MDSC were significantly higher in alive group and none-ARDS group, and they two were correlated most (Spearman r = 0.69 p<0.01). Among 479 patients in validating cohort, higher CX3CR1 was associated with better 28-day survival benefit (hazard ratio [HR] 2.657, 95% CI 1.838-3.843) and higher MDSC associated with better 28-day survival benefit (HR 2.205, 95% CI 1.516-2.206). Using the gene modules of WGCNA that correlated most with CX3CR1 expression level and MDSC proliferation level, biological processes of T cell cytokine production and regulation of glial cell migration were significantly enriched. We demonstrated that CX3CR1 and MDSC can predict ARDS risk and contribute survival benefit for sepsis patients. MDSC might be important component of the immune micro-environment and should be integrated into predictive biomarker panels for immune therapy and be validated in future prospective clinical trials.