The tissue-specific protumorigenic impact of type 17 T cells in pancreatic ductal adenocarcinoma and ovarian cancer microenvironments
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Philipps-Universität Marburg
Abstract
This thesis discusses the protumorigenic impact of Tc17 and Th17 cells on the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer (OC).
Tc17 cells and their functions in PDAC have not been investigated so far. Here, we describe how Tc17 cells enhance tumor progression in this context. High levels of Tc17 in PDAC exhibited a strong correlation with tumor staging and reduced patient survival.
Tc17 cells, through the synergistic action of IL-17A and TNF, induced the differentiation of inflammatory cancer-associated fibroblasts (iCAF). Co-culture of pancreatic tumor cells with Tc17-iCAFs resulted in increased proliferation and elevated expression of antiapoptotic, as well as proliferation- and, metabolism-, associated genes. In different mouse models, we could confirm in vivo the tumor growth-promoting effect of Tc17-iCAFs on murine and human tumors, which was dependent on IL-17RA expression.
In OC, the prognostic value and the influence of Th17 cells on the TME is controversially discussed. Here, we demonstrated enrichment of Th17 cells in early omental metastases. Additionally, we identified mesothelial cells as targets for the classical Th17 cytokines, IL-17A and TNF. In primary omental mesothelial cells (MESO), IL-17A and TNF synergistically induce mesenchymal transition and an inflammatory phenotype. This phenotype was partially confirmed ex vivo via single-cell RNA sequencing. IL-17A and TNF disrupted the mesothelial monolayer integrity by downregulating tight-junction protein 1 (ZO1) expression and enhanced expression of the adhesion molecule VCAM-1. These changes facilitated increased attachment of tumor cells to the monolayer. As a positive feedback loop, the MESO secretome after IL-17A and TNF stimulation promoted differentiation of Th17 cells. In summary, we identified two novel, tissue-specific mechanisms of how different IL-17Aand
TNF-secreting cell populations mediate their protumorigenic properties via different players of the TME, fibroblasts and mesothelial cells, in PDAC, respectively OC.