Targeting Tumor-Stromal IL6/STAT3 Signaling through IL1 Receptor Inhibition in Pancreatic Cancer.

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense, desmoplastic stroma and the consequent altered interactions between cancer cells and their surrounding tumor microenvironment (TME) that promote disease progression, metastasis, and chemoresistance. We have previously shown that IL-6 secreted from pancreatic stellate cells (PSCs) stimulates the activation of STAT3 signaling in tumor cells, an established mechanism of therapeutic resistance in PDAC. We have now identified the tumor cell-derived cytokine interleukin-1α (IL-1α) as an upstream mediator of IL-6 release from PSCs that is involved in STAT3 activation within the TME. Herein, we show that IL-1α is overexpressed in both murine and human PDAC tumors and engages with its cognate receptor IL-1R1 which is strongly expressed on stromal cells. Further, we show that IL-1R1 inhibition using anakinra (recombinant IL-1 receptor antagonist) significantly reduces stromal-derived IL-6, thereby suppressing IL-6-dependent STAT3 activation in human PDAC cell lines. Anakinra treatment results in significant reduction in IL-6 and activated STAT3 levels in pancreatic tumors from Ptf1aCre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice. Additionally, the combination of anakinra with cytotoxic chemotherapy significantly extends overall survival compared with vehicle treatment or anakinra monotherapy in this aggressive genetic mouse model of PDAC. These data highlight the importance of IL-1 in mediating tumor-stromal IL-6/STAT3 crosstalk in the TME and provide preclinical rationale for targeting IL-1 signaling as a therapeutic strategy in PDAC.