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

Abstract

Background: Macrophage 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 Methods: We 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. Results: According 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. Conclusions: Overall, 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.