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

• Published in: The Journal of thoracic and cardiovascular surgery Vol. 148; no. 4; pp. 1208 - 1216.e2
• Main Authors: Pei, Bao-xiang, MD, Sun, Bing-sheng, MD, PhD, Zhang, Zhen-fa, MD, PhD, Wang, An-lei, MD, Ren, Peng, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2014
• Subjects: Aged; Biomarkers, Tumor - metabolism; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cardiothoracic Surgery; Female; Humans; Immunoenzyme Techniques; Interleukin-6 - metabolism; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Macrophage Colony-Stimulating Factor - metabolism; Macrophages, Alveolar - metabolism; Male; Middle Aged; Prognosis; Risk Factors; Tissue Array Analysis; TAM; NSCLC; OS; tissue microarray; colony-stimulating factor-1; non–small cell lung cancer; tumor-associated macrophage; TMA; +; positive; CSF-1; IL-6; interleukin-6; DFS; 10.4; 11.3; −; negative; 10.2; disease-free survival; 10.1; overall survival
• ISSN: 0022-5223; 1097-685X
• DOI: 10.1016/j.jtcvs.2014.05.003

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.