Roquin-deficient T cells drive pancreatitis and tumorigenesis through IL-17 and Th17-inappropriate Cytokine production
Pancreatitis can trigger pancreatic ductal adenocarcinoma (PDAC), however, the underlying origins can be diverse and cellular and molecular mechanisms remain elusive. We show that combined genetic inactivation of the RNA-binding proteins Roquin-1 and Roquin-2 in T cells induced pancreatitis, pancreatic neoplasia and accelerated PDAC formation, if KrasG12D was expressed in acinar cells. In the pancreas, Roquin-deficient T cells were highly activated, recruited proinflammatory neutrophils via IL-17A secretion, and inappropriately produced G-CSF that, in a feed-forward loop, further induced and mobilized neutrophils. Consistently, neutralization of IL-17 or G-CSF ameliorated pancreas pathology. Roquin repressed G-CSF in two ways. It directly inhibited CSF3 mRNA expression through its 3'-UTR, and indirectly, because Roquin loss-of-function imposed transcriptional reprogramming by NF-kB and established an active enhancer at the Csf3 locus in Th17 cells. Together, we identified critical cellular and humoral components and epigenetic, transcriptional and post-transcriptional mechanisms within a regulatory circuit that prevents pancreatic cancer formation. Overall design: RNAseq in primary pancreas cancer cell lines and primary cancer tissue taken from KrasG12D, p48cre mice reconstituted with either WT or DKOT bone marrow.