Tumor-derived TGF-{beta} alters the ability of plasmacytoid dendritic cells to respond to innate immune signaling

A growing number of observations has suggested that plasmacytoid dendritic cells (pDC) play a critical role in tumor biology. In patients, infiltration of tumors by pDC generally correlates with a poor prognosis, suggesting that pDC may play an important role in the host-tumor relationship. Here we analyze the influence of pDC in solid tumor development using two different tumor models: TC-1 and B16-OVA. Phenotypic and functional gene profiling analysis of tumor-associated pDC showed that the tumor microenvironment affected their activation status and ability to produce cytokines and chemokines. In addition, tumor cells secreted factors that inhibit the ability of pDC to produce type I IFN. Among the various cytokines and chemokines produced by the tumor cells, we demonstrate that TGF-β is the main factor responsible for this inhibition. Using a mouse model deficient for pDCs, we also show that pDCs promote TC-1 tumor growth and that NK cells and regulatory T cells are involved in the protumoral effect of pDCs. Overall, our results evidence the crosstalk among pDCs, NK and regulatory T cells in the promotion of tumor growth and their role in the development of anti-tumor immune responses.

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