Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer

Background: High circulating neutrophil-lymphocyte ratio (NLR) appears to be prognostic in metastatic colorectal cancer (mCRC). We investigated the relationship of NLR with circulating cytokines and molecular alterations. Methods: We performed retrospective analyses on multiple cohorts of CRC patients (metastatic untreated (n = 166), refractory metastatic (n = 161), hepatectomy (n = 198), stage 2/3 (n = 274), and molecularly screened (n = 342)). High NLR (ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood) was defined as NLR>5. Plasma cytokines were evaluated using multiplex-bead assays. Kaplan-Meier estimates, non-parametric correlation analysis, and hierarchical cluster analyses were used. Results: High NLR was associated with poor prognosis in mCRC (hazard ratio (HR) 1.73; 95% confidence interval (CI): 1.03-2.89; P = 0.039) independent of known prognostic factors and molecular alterations (KRAS/NRAS/BRAF/PIK3CA/CIMP). High NLR correlated with increased expression of interleukin 6 (IL-6), IL-8, IL-2R alpha, hepatocyte growth factor, macrophage-colony stimulating factor, and vascular epidermal growth factor in exploratory (n = 39) and validation (n = 166) cohorts. Fourteen additional cytokines correlated with high NLR in the validation cohort. All 20 cytokines fell into three major clusters: inflammatory cytokines, angiogenic cytokines, and epidermal growth factor ligands. In mCRC, composite stratification based on NLR-cytokine score provided enhanced prognostic information (HR 2.09; 95% CI: 1.59-2.76; P<0.001) over and above NLR. Conclusions: High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis. A composite NLR-cytokine stratification has enhanced prognostic value in mCRC.