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Tumor Cell-Derived IL-1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy typified by a highly stromal and weakly immunogenic tumor microenvironment that promotes tumor evolution and contributes to therapeutic resistance. Here, we demonstrate that PDA tumor cell-derived pro-inflammatory cytokine, interleukin-1β (IL-1β) is essential for the establishment of the pro-tumorigenic PDA microenvironment. Tumor cell-derived IL-1β promoted the activation and secretory phenotype of quiescent pancreatic stellate cells (PSC) and established an immunosuppressive milieu mediated by M2 macrophages, MDSCs, CD1dhiCD5+ regulatory B cells and Th17 cells. Loss of tumor cell-derived IL-1 signaling in tumor stroma enabled intra-tumoral infiltration and activation of CD8+ cytotoxic T cells, attenuated growth of pancreatic neoplasia and conferred survival advantage to PDA bearing mice. Accordingly, antibody-mediated neutralization of IL-1β significantly enhanced the anti-tumor activity of α-PD-1, and was accompanied by increased tumor infiltration of CD8+ T cells. Tumor cell expression of IL-1β in vivo was driven by microbial-dependent activation of toll-like receptor 4 (TLR4) signaling and subsequent engagement of the NLRP3 inflammasome. Collectively, these findings identify a hitherto unappreciated role for tumor cell-derived IL-1β in orchestrating an immune modulatory program that supports pancreatic tumorigenesis.