The Prognstic Significance And Mechanism Of Mast Cell-derived Inteleukin-17in Gastric Cancer Patients

PurposeInteleukin-17, one of the most important components of the immune system in inflammation, is prevalent in tumor tissue and suppresses effective anti-tumor immune responses. The aim of this study was to explore the source, distribution, functional relevance and predictive value of the tumor-infiltrating1L-17and the potential mechanism of its contribution to tumor progression in human gastric cancer.MethodsIn total,112patients who underwent curative resection between February2009and March2010in our hospital were enrolled. Immunofluorescence was used to evaluate the colocalization of CD3, CD4, CD56, CD20, CD68, and mast cell tryptase (MCT) with IL-17. Immunohistochemistry was used to evaluate the distribution of microvessel densities, neutrophils, macrophages and regulatory T cells in different microanatomical areas. T tests or Mann-Whitney tests were used to compare the distribution of immune and inflammatory mediators between tumor and normal tissues. Correlations were analyzed by using Pearson or Spearman tests. Survival function was determined by Kaplan-Meier analysis and log-rank test. Multivariate analysis was performed by Cox proportional hazards models with the backward likelihood stepwise procedures.ResultsMost IL-17+cells colocalized with MCT*cells, while the mean percentages of CD3+IL-17+and CD4+IL-17+cells were12.4%and8.4%. Significant positive correlations were detected between densities of mast cell-derived IL-17and microvessel densities (r=0.4396, P<0.0001), although significant, but weak, correlations were found between mast cell-derived IL-17and neutrophils (r=0.2578, P=0.0061), and regulatory T cells (r=0.2898, P=0.0021). Furthermore, we found that the majority of vascular endothelial cells expressing IL-17R, however, barely neutrophils, macrophages and regulatory T cells were detected expressing IL-17R. Increasing intratumor infiltrated MCTWls, IL-17+cells and MCT+/IL-17+cells, were significantly associated with worse overall survival. Multivariate analysis revealed that intratumor MCT*cells were independent prognostic factors, similar to conventional clinicopathological features, such as degree TNM stage.ConclusionsOur results indicated that mast cells were the major source of IL-17in gastric cancer, and intratumor IL-17infiltration may have promoted tumor progression by enhancing angiogenesis in the tumor microenvironment through the axis of IL-17/IL-17R. IL-17-positive mast cells showed an prognostic factor in gastric cancer, indicating that immunotherapy targeting mast cells might be an effective strategy to control intratumor IL-17infiltration, and consequently reverse immunosuppression in the tumor microenvironment, facilitating cancer immunotherapy.