Tumor-associated macrophage infiltration is associated with a higher rate of tumor spread through air spaces in resected lung adenocarcinomas

[Display omitted] •Lung cancer can be spread through air spaces (STAS), a recognized phenomenon.•Tumor-associated macrophages (TAMs) favor tumor progression.•CD68 + TAMs are an independent predictor of a high STAS rate. Lung cancer can spread in numerous ways, one of which has been suggested to be spread through air spaces (STAS). The tumor immune microenvironment appears to play a significant role in this spread. Particularly, tumor-associated macrophages (TAMs) can create a favorable microenvironment for tumor progression. In this study, we analyzed data from 709 patients with stage 0–IIIA lung adenocarcinoma, resected between 1999 and 2016, and investigated whether immune cell infiltration was associated with the occurrence of STAS and clinical outcome of the disease. Tissue microarrays were constructed, and immunohistochemical analysis was performed for CD3, CD4, CD8, CD45RO, CD25, CD20, and CD68. The three tumor areas with the highest density of immune cells were photographed, and the immune cells were quantified. Associations between variables were analyzed using chi-square tests and Mann–Whitney U tests. Recurrence-free probability and overall survival were analyzed using log-rank tests and Cox proportional hazards models. After analyzing the associations between STAS and each type of immune cell infiltration, high density of CD68 + TAMs was identified as an independent predictor of a high STAS rate (p = 0.014) and was found to be associated with a high risk of recurrence, using univariate analysis (p = 0.008). After adjusting for CD68+ TAMs, pathological stage, and lymphovascular invasion, STAS remained significantly associated with a high risk of recurrence (HR = 3.50, p < 0.001). We demonstrated that a high density of CD68 + TAMs is an independent predictor of an increased STAS rate. Additionally, STAS is correlated with aggressive tumor behavior characteristics.