Interstitial tumor-associated macrophages combined with tumor-derived colony-stimulating factor-1 and interleukin-6, a novel prognostic biomarker in non-small cell lung cancer

Abstract

Objectives: Recent experimental evidence has indicated that interstitial tumor-associated macrophages (TAMs), tumor-derived macrophage colony-stimulating factor (also known as CSF-1), and interleukin-6 (IL-6) interact in the pathogenesis of malignant epithelial tumors, including lung cancer. The present study aimed to explore their relationship and prognostic significance in surgically resected non-small cell lung cancer (NSCLC).

Methods: Tissue microarray and immunohistochemistry were used to detect the expression of CSF-1, IL-6, and CD68-positive TAMs in 417 patients with NSCLC undergoing complete pulmonary resection from 2003 to 2008. Their correlations and clinicopathologic data were analyzed using chi-square testing. Their prognostic values were evaluated by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis.

Results: The expression of CSF-1 and IL-6 in NSCLC correlated positively with the infiltration degree of TAMs in the tumor stroma (r=0.184 and r=0.196, respectively; P<.001). The expression of both CSF-1 and IL-6 was statistically significant for survival (P<.001). Nevertheless, no such relationship was observed for CD68 in the tumor stroma (P>.05). When CSF-1 and/or IL-6 and CD68 were taken into consideration together, the result became statistically significant. Multivariate analysis showed that co-expression of CD68, CSF-1, and IL-6 remained the most significant and independent prognostic factor for survival (P<.05) but not the combinations of CSF-1 and IL-6, CD68 and CSF-1, or CD68 and IL-6 (P>.05). The 5-year survival rate in the CD68-negative and CSF-1- and IL-6-positive group was better than the rate in the CD68, CSF-1-, and IL-6-positive group (P<.05).

Conclusions: The combination of CD68 plus TAMs, CSF-1, and IL-6 is very likely to be a valuable independent predictor of survival in patients with NSCLC. Perhaps co-expression of CSF-1 and IL-6 induces interstitial TAMs to shift toward the tumor-promoting phenotype.