Intratumor IL-17-Positive Mast Cells Are the Major Source of the IL-17 That Is Predictive of Survival in Gastric Cancer Patients

Abstract

Interleukin-17 (IL-17) is prevalent in tumor tissue and suppresses effective anti-tumor immune responses. However, the source of the increased tumor-infiltrating IL-17 and its contribution to tumor progression in human gastric cancer remain poorly understood. In this study, we enrolled 112 gastric cancer patients, 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 density (CD34), CD66b+, CD68+, and FoxP3+ cells in different microanatomical areas. Prognostic value was determined by Kaplan-Meier analysis and a Cox regression model. The results showed that mast cells, but not T cells or macrophages, were the predominant cell type producing IL-17 in gastric cancer. Significant positive correlations were detected between densities of mast cell-derived IL-17 and microvessels, neutrophils, and regulatory T cells (Tregs). Futhermore, we found that the majority of vascular endothelial cells expressing Interleukin-17 receptor (IL-17R). Kaplan-Meier analysis revealed that increasing intratumor infiltrated mast cells and IL-17+ cells, as well as MCT+ IL-17+ cells, were significantly associated with worse overall survival. These findings indicated that mast cells were the major source of IL-17 in gastric cancer, and intratumor IL-17 infiltration 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 a prognostic factor in gastric cancer, indicating that immunotherapy targeting mast cells might be an effective strategy to control intratumor IL-17 infiltration, and consequently reverse immunosuppression in the tumor microenvironment, facilitating cancer immunotherapy.

FoxP3+ regulatory T cells, interleukin 17 and mast cells in chronic inflammatory periodontal disease

“…The finding that that the IL17A + cells were not T cells and hence not Th17 cells was surprising. However, it is becoming increasingly clear that IL17A expressing cells in a number of lesions including rheumatoid arthritis synovium, psoriasis, renal allograft rejection, atherosclerosis and some tumors, have an ovoid/plasmacytoid irregular morphology and are tryptase‐positive mast cells . In this context, the present study has clearly demonstrated that mast cells are key producers of IL17 in periodontal disease tissues.…”

Mast Cells Comprise the Major of Interleukin 17-Producing Cells and Predict a Poor Prognosis in Hepatocellular Carcinoma

“…8,24,25 Interestingly, the levels of intratumoral IL-17-producing cells were strong positively correlated with microvessel density in HCC. So far as we known, our finding was the first report in HCC.…”

The correlations between IL-17 vs. Th17 cells and cancer patient survival: a systematic review

“…CLL D chronic lymphocytic leukemia; AC D adenocarcinoma; CRC D colorectal carcinoma; HCC D hepatocellular carcinoma; NA D not applicable or not mentioned in the article; NSCLC D non-small cell lung carcinoma. 15,16,[18][19][20]30,37,[40][41][42][43][44][45][46][47][48][49][50] Five studies reported on a correlation between a high number of IL-17 C cells and improved survival. 21,28,29,51,52 It is important to note that in two of these five studies, the IL-17 C cells were scored in areas with the densest lymphocytic infiltrate, one of which was on pancreatic ductal adenocarcinoma patients who had received immunotherapy (the correlation between IL-17 and survival was based on 12 patients).…”