Prognostic Impact of Tumor-Associated Macrophage-Related Markers in Patients with Adenocarcinoma of the Lung

Abstract

BackgroundMacrophage polarization is an important pathogenetic factor in neoplastic diseases. Phosphorylated signal transducer and activator of transcription 1 (phospho-STAT1) regulates the M1 phenotype, and c-Maf regulates the M2 phenotype. However, the role of macrophage phenotype in lung adenocarcinoma (LAD) remains unclear.Patients and MethodsWe examined whether the density of M1 and M2 macrophages was associated with prognosis in patients with LAD using double-labeling immunohistochemistry. In addition, programmed death ligand 1 (PD-L1) expression was investigated. Immune cells coexpressing CD68 and phospho-STAT1 were considered M1 macrophages, whereas those coexpressing CD68 and c-Maf were recognized as M2 macrophages. Patients with LAD (N = 307) were divided into two cohorts (n = 100 and n = 207) to evaluate the associations of M1 and M2 phenotypes with prognosis in patients with LAD. We determined the cut-off values of CD68/phospho-STAT1-positive cells and CD68/c-Maf-positive cells to assess correlations with overall survival (OS) using receiver operating characteristic curve analysis in the first cohort.ResultsAccording to the cut-off values of 5 or less CD68/phospho-STAT1-positive cells and more than 11 CD68/c-Maf-positive cells, high expression of CD68/c-Maf and low expression of CD68/Phospho-STAT1 were identified as independent prognostic markers for OS and disease-free survival (DFS). Moreover, the M1/M2 ratio (0.19 or less) was a poor prognostic factor for OS and DFS. However, PD-L1 expression did not correlate with patient outcomes.ConclusionsOverall, these findings suggest that double immunostaining of markers of phospho-STAT1 (M1) and c-Maf (M2) can be used as prognostic indicators for patients with LAD.