ASO Visual Abstract: Prognostic Impact of Tumor-Associated Macrophage-Related Markers in Patients with Adenocarcinoma of the Lung

Abstract Macrophage polarization is an important pathogenetic factor in neoplastic diseases and is regulated by transcription factors, i.e., phosphorylated signal transducer and activator of transcription 1 (phospho-STAT1) for the M1 phenotype and c-Maf for the M2 phenotype. However, the role of macrophage phenotype in lung adenocarcinoma (LAD) remains unclear. Here, we examined whether the density of M1 and M2 macrophages was associated with prognosis in patients with LAD using double-labeling immunohistochemistry for the detection of macrophage markers. Additionally, programmed death ligand 1 (PD-L1) expression was investigated. Immune cells co-expressing CD68 and phospho-STAT1 were considered M1 macrophages, whereas those co-expressing CD68 and c-Maf were recognized as M2 macrophages. Three hundred seven patients with LAD were divided into two cohorts (N = 100 and 207 cases, respectively) 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 (5 or less) and CD68/c-Maf-positive cells (more than 11) to assess correlations with survival using receiver operating characteristic curve analysis in the first cohort. According to the cut-off values, high expression of CD68/c-Maf was identified as an independent prognostic marker, whereas CD68/Phospho-STAT1 expression was inversely correlated with patient outcomes. Moreover, the M1/M2 ratio (0.19 or less) was a poor prognostic factor for LAD. However, PD-L1 expression was not correlated with patient outcomes. Overall, these findings suggested that double staining of markers identifying M1 and M2 macrophages, including phospho-STAT1 and c-Maf, can be used as prognostic indicators for patients with LAD.