Background: Inflammation is a crucial regulator of the carcinogenic process and response to therapy. Our group has identified a clinically applicable inflammatory biomarker, the Neutrophil- Lymphocyte Ratio (NLR), that predicts treatment response and overall survival in patients with advanced colorectal. Elevated NLR is thought to reflect a more aggressive tumour phenotype leading to more systemic inflammation. However, this hypothesis remains untested.
Aim: To identify the role of the tumour microenvironment, in terms of immune infiltrate and necrosis, in determining NLR in patients with advanced colorectal cancer.
Methods: Patient FFPE tumour blocks from an independent cohort of 145 patients with stage C or D CRC that underwent 5FU-based clinical trials were included in this analysis. Tissue microarrays were constructed and analysed immunohistochemically for inflammatory markers (CD8, CD15, CD68) and necrotic pathways (HMGB1, MyD88). Regression analysis between tumour characteristics and NLR was conducted in SPSS.
Results: Elevated NLR was present in 25% patients and correlated with shorter time to progression and survival in this study (P<0.001). Higher NLR was due mainly to higher circulating neutrophils, rather than lower lymphocytes. Necrotic signaling was associated with increased numbers of CD15+ neutrophils, CD68+ macrophages and CD8+ T cells (p<0.01). NLR was not correlated directly with any immune cell or necrotic markers. However, female gender and presence of liver and lung metastatic disease were significantly associated with high NLR (p<0.05). Patients with metastatic disease also had higher expression of necrotic markers and immune infiltrates.
Conclusion: In CRC patients with more advanced/aggressive disease there is a relationship between tumoural and systemic immune response that leads to disease progression and poorer survival. Further investigation of this relationship is currently being investigated using proteomic techniques.