High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma

BackgroundTumor-associated immune factors are heterogeneous and play an important role in determining outcome in cancer patients. In this study, the expression levels of immune factors in tumor tissue-conditioned media from lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) were analyzed. MethodsLUAD and LUSC tissue specimens were collected immediately after surgery for antibody array analysis and real-time quantitative PCR. ResultsHigher levels of chemokines MCP1/CCL2 (21.11-fold increase) and MIP-1/CCL4 (19.33-fold increase) were identified in LUAD than in LUSC. Western blot and quantitative real-time PCR analyses showed higher co-expression of CCL2 and CCL4 in LUAD tissues compared to LUSC (P<0.0001). Immunofluorescent co-staining showed a high percentage of CCL2(+)/CD68(+) and CCL4(+)/CD68(+) tumor-associated macrophages in LUAD compared to LUSC tissues, which might be responsible for the higher expression of CCL2 and CCL4 in LUAD samples. Kaplan-Meier curves showed that CCL2 overexpression in patients with LUSC was associated with beneficial overall survival (OS; P=0.048) and progression-free survival (PFS; P=0.012); however, LUAD patients with higher CCL2 expression had unfavorable OS (P=6.7e-08) and PFS (P=0.00098). Similarly, CCL4 overexpression predicted favorable PFS (P=0.021) in patients with LUSC, but patients with high CCL4 levels in LUAD had shorter OS (P=0.013). ConclusionOur study revealed that CCL2 and CCL4 expression levels could serve as potential prognostic biomarkers and therapeutic targets for NSCLC patients.