P2.01-040 CXC Chemokine Receptor 3 and ELR Motif Negative CXC Chemokine Ligand Axis in Non-Small Cell Lung Cancer

Topic: Proteins in Lung Cancer and Proteomics


      CXC group chemokine receptors and ligands are well known for their role in immune response, regulation of angiogenesis, tumor development and growth. Understanding of lung cancer pathogenesis requires comprehensive analysis of cell interaction in tumor microenvironment formed by malignant cells, stromal cells and immune cell infiltrate. CXC chemokine receptor 3 (CXCR3) and ELR motif negative CXC chemokine ligands 4, 9, 10 and 11 (CXCL4, CXCL9, CXCL10 and CXCL11) form an axis which is part of complex tumorigenesis process.


      The study recruited 38 patients with NSCLC ranging from stage IA to IIA undergoing anatomical pulmonary resection between January 2011 and January 2012. Patients were followed to assess relapse rate and survival. CXCR3 expression and tumor infiltrating immune cells (neutrophils, T helper cells - CD4, cytotoxic T lymphocytes - CD8, B cells - CD20, macrophages - CD68 and plasma cells - CD138) were evaluated in resected tumor specimens by immunohistochemistry. For CXCR3 basic annotation parameters included an evaluation of staining intensity (negative, weak, moderate or strong) and fraction of stained cells (rare, <25%, 25-75% or >75%). Blood samples from peripheral vein and from pulmonary vein draining tumor vascular bed were collected at the time of surgery. Levels of CXCL4, CXCL9, CXCL10 and CXCL11 were measured using ELISA and CXCL gradient was calculated. Pearson test was used to assess statistical relationship between CXCL levels, CXCR expression and immune cell infiltrate.


      Majority of tumor specimens despite heterogeneity showed strong CXCR3 expression which was equally intense in tumor cells and stroma. Correlation between tumoral and stromal expression was very strong (r = 0.86, p < 0.001). Tumoral expression of CXCR3 correlated with total number of tumor infiltrating immune cells (r = -0.58, p < 0.01), number of T helper cells (r = -0.5, p = 0.01) and T cytotoxic cells (r = -0.4, p < 0.05). Stromal CXCR3 expression had similar correlation with aforementioned parameters but also included correlation with number of B cells in infiltrate (r = -0.45, p = 0.01). CXCL10 and CXCL11 gradients correlated with stromal CXCR3 expression (r = 0.42, p < 0.05 and r = -0.42, p < 0.05). Moderate statistically significant correlation was found between CXCL4 and CXCL10 gradients and relapse (r=0.39, r=0.35, p<0.05).


      CXCR3 and ELR motif negative CXC chemokine axis plays role in lung cancer pathogenesis and needs further evaluation for better understanding of tumor immunology.


      CXC chemokines, CXCR3, Tumor immunology