Abstract
BackgroundThe tumour microenvironment comprises a network of immune response and vascularization factors. From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. We subsequently determined which factors were correlated with patient survival in cervical carcinoma.MethodsThe expression of 42 genes was investigated in 52 fresh frozen squamous cervical cancer samples by qRT-PCR. Weighted gene co-expression network analysis and mixed-model analyses were performed to identify gene expression clusters. Correlations and survival analyses were further studied at expression cluster and single gene level.ResultsWe identified four immune response clusters: ‘T cells’ (CD3E/CD8A/TBX21/IFNG/FOXP3/IDO1), ‘Macrophages’ (CD4/CD14/CD163), ‘Th2’ (IL4/IL5/IL13/IL12) and ‘Inflammation’ (IL6/IL1B/IL8/IL23/IL10/ARG1) and two vascularization clusters: ‘Angiogenesis’ (VEGFA/FLT1/ANGPT2/ PGF/ICAM1) and ‘Vessel maturation’ (PECAM1/VCAM1/ANGPT1/SELE/KDR/LGALS9). The ‘T cells’ module was correlated with all modules except for ‘Inflammation’, while ‘Inflammation’ was most significantly correlated with ‘Angiogenesis’ (p < 0.001). High expression of the ‘T cells’ cluster was correlated with earlier TNM stage (p = 0.007). High CD3E expression was correlated with improved disease-specific survival (p = 0.022), while high VEGFA expression was correlated with poor disease-specific survival (p = 0.032). Independent predictors of poor disease-specific survival were IL6 (hazard ratio = 2.3, p = 0.011) and a high IL6/IL17 ratio combined with low IL5 expression (hazard ratio = 4.2, p = 0.010).Conclusions‘Inflammation’ marker IL6, especially in combination with low levels of IL5 and IL17, was correlated with poor survival. This suggests that IL6 promotes tumour growth, which may be suppressed by a Th17 and Th2 response. Measuring IL6, IL5 and IL17 expression may improve the accuracy of predicting prognosis in cervical cancer.
Highlights
The tumour microenvironment comprises a network of immune response and vascularization factors
Gene clustering We investigated the expression of 27 immune response and 15 vascularization marker genes in 52 squamous cervical cancer samples by weighted gene co-expression network analysis (WGCNA), a method developed for network analysis of gene expression data [18]
Additional clustering was found for the T cell (CD3E), CD8+ T lymphocytes (CTL) (CD8A), T helper 1 (Th1) (TBX21, IFNG) and Regulatory T cells (Tregs) (FOXP3, IDO1) markers
Summary
The tumour microenvironment comprises a network of immune response and vascularization factors From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. Tumour infiltrating T lymphocytes have been shown to be an independent predictor for survival in ovarian and colorectal cancer [3,4]. Synthetic long-peptide vaccination in women with HPV16+ high-grade vulvar intraepithelial neoplasia has been shown to induce CD4+ T helper and CD8+ CTL responses, which were correlated with tumour regression [5]. We have previously shown that a low number of CTL combined with a high number of Tregs is an independent predictor for poor survival [6]. A Th2-induced immune response has been shown to support cervical cancer progression [9]. The role of Th17 cells in cancer is still unclear, as they are capable of inducing both tumour growth and tumour regression [10]
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