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Abstract

BackgroundIL-17A and TNF synergistically promote inflammation and tumorigenesis. Their interplay and impact on ovarian carcinoma (OC) progression are, however, poorly understood. We addressed this question focusing on mesothelial cells, whose interaction with tumor cells is known to play a pivotal role in transcoelomic metastasis formation.MethodsFlow-cytometry and immunohistochemistry experiments were employed to identify cellular sources of IL-17A and TNF. Changes in transcriptomes and secretomes were determined by bulk and single cell RNA sequencing as well as affinity proteomics. Functional consequences were investigated by microscopic analyses and tumor cell adhesion assays. Potential clinical implications were assessed by immunohistochemistry and survival analyses.ResultsWe identified Th17 cells as the main population of IL-17A- and TNF producers in ascites and detected their accumulation in early omental metastases. Both IL-17A and its receptor subunit IL-17RC were associated with short survival of OC patients, pointing to a role in clinical progression. IL-17A and TNF synergistically induced the reprogramming of mesothelial cells towards a pro-inflammatory mesenchymal phenotype, concomitantly with a loss of tight junctions and an impairment of mesothelial monolayer integrity, thereby promoting cancer cell adhesion. IL-17A and TNF synergistically induced the Th17-promoting cytokines IL-6 and IL-1 beta as well as the Th17-attracting chemokine CCL20 in mesothelial cells, indicating a reciprocal crosstalk that potentiates the tumor-promoting role of Th17 cells in OC.ConclusionsOur findings reveal a novel function for Th17 cells in the OC microenvironment, which entails the IL-17A/TNF-mediated induction of mesothelial-mesenchymal transition, disruption of mesothelial layer integrity and consequently promotion of OC cell adhesion. These effects are potentiated by a positive feedback loop between mesothelial and Th17 cells. Together with the observed clinical associations and accumulation of Th17 cells in omental micrometastases, our observations point to a potential role in early metastases formation and thus to new therapeutic options.
A decisive step in ovarian carcinoma metastasis is breaching the protective mesothelial monolayer covering the peritoneal organs. This study has uncovered a hitherto unknown mechanism involving the induction of mesenchymal reprogramming by the synergistic action of IL-17A and TNF produced by Th17 cells, which renders the mesothelial monolayer susceptible to cancer cell adhesion. These reprogrammed mesothelial cells also secrete Th17-promoting mediators, thereby establishing a positive feedback loop that amplifies the impact of IL-17A and TNF on mesothelial cells. Disruption of this reciprocal crosstalk may represent a promising strategy to interfere with metastatic spreading.Ovarian carcinoma metastasis is promoted by reciprocal crosstalk of Th17, mesothelial and cancer cells. image