Tumor-distant pulmonary immune landscapes are associated with postoperative outcomes in non-small cell lung cancer.

Background: While antitumor immunity in lung cancer is typically evaluated within the tumor microenvironment and regional lymphoid organs, immune features in non-tumorous lung tissue-particularly at sites distant from the primary tumor-may also reflect host-related pulmonary immune characteristics. However, the clinical relevance of immune cell abundance in such tumor-distant lung parenchyma remains unclear. Therefore, this study aimed to investigate whether immune cell abundance in tumor-distant non-tumorous lung tissue is associated with clinicopathological features and postoperative outcomes in patients with non-small cell lung cancer (NSCLC). Methods: This retrospective observational study included 40 patients with NSCLC who underwent curative lobectomy and had paired tumor-near and tumor-distant lung tissue specimens available for analysis. Immunohistochemical staining for dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-positive cells and CD169-positive macrophages was performed, and immune cell counts were quantified using a hotspot counting method. Associations between immune cell counts, clinicopathological variables, smoking exposure, and recurrence-free survival (RFS) were analyzed. Results: Both DC-SIGN-positive cells and CD169-positive macrophages were significantly more abundant in tumor-near lung tissue than in tumor-distant tissue. However, only DC-SIGN-positive cell counts in tumor-distant lung parenchyma were associated with postoperative recurrence. Higher numbers of DC-SIGN-positive cells in tumor-distant specimens were associated with favorable RFS in univariate analysis, although this association did not remain statistically significant after propensity score (PS) adjustment, whereas immune cell counts in tumor-near tissue showed no clear association with postoperative outcomes. Tumor-distant DC-SIGN-positive cell counts were lower in patients with advanced pathological stage and tended to be reduced in those with lymph node metastasis. In contrast, CD169-positive macrophage counts were strongly associated with smoking exposure but were not related to RFS in either spatial compartment. Conclusions: Lower abundance of DC-SIGN-positive cells in tumor-distant, non-tumorous lung parenchyma was associated with more advanced pathological features and postoperative recurrence, suggesting inter-individual variability in pulmonary interstitial immune cell distribution beyond the tumor microenvironment. These findings support the possibility that inter-individual differences in tumor-distant pulmonary immune landscapes may be associated with advanced pathological features and postoperative recurrence.