Regulation of NK cells through extracellular vesicles and microbiota released metabolites in PDAC

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The critical role of NK cells in tumor immunosurveillance is widely accepted, but the tumor-dependent suppression of NK cell activity in PDAC and consequently NK cell-based immunotherapies are relatively underexplored. Within the first funding period we investigated the biogenesis of extracellular vesicles released by tumor cells and their impact on NK cell functions. We established that EV biogenesis depends on the activity of the chaperone/NK cell-ligand NKp30 via the CBP/p300/p53 axis. Frequent dysfunction of this pathway due to P53 mutations leads to the release of EVs with specific cargo loading associated with reported pro-tumorigenic activity in PDAC (MIF, glypican-1) and factors (actin-binding proteins, MyHII) that were so far not described in PDAC-EVs. These EVs inhibited NK cell cytotoxicity and instead promoted an exhaustion phenotype in NK cells from healthy donors. Based on this data we will dissect EV-mediated in vivo mechanisms, which reprogram NK cells within the immune suppressive and tumor-promoting PDAC-microenvironment (TME) using a Pan02-transplantation model. The phenotype and the activity of tumor associated NK cells (TANK) will be analyzed in detail and the potential of identified EV-associated factors as biomarkers will be analyzed. Expected results will be validated in human samples. Recently, the crucial role of intestinal and intratumoral bacteria for the anti-tumor immune responses in PDAC was reported. Preliminary own data suggest that short chain fatty acids (SCFAs) and bacterial vesicles released by the microbiota impair NK cell activity. Thus the cross-talk of SCFAs and EVs in regulating NK cells will be analyzed. Perpectively, the data obtained will be used to design therapeutic EVs which are able to overcome NK cell-inhibition and instead stimulate NK cell activity to improve NK cell-based immunotherapies for PDAC.