TUMOR CELL-DERIVED IL-1β PROMOTES DESMOPLASIA AND IMMUNE SUPPRESSION IN PANCREATIC CANCER

• Published in: Cancer research (Chicago, Ill.) Vol. 80; no. 5; pp. 1088 - 1101
• Main Authors: Das, Shipra, Shapiro, Beny, Vucic, Emily A., Vogt, Sandra, Bar-Sagi, Dafna
• Format: Journal Article
• Language: English
• Published: 08-01-2020
• DOI: 10.1158/0008-5472.CAN-19-2080
• EISSN: 1538-7445
• ISSN: 0008-5472

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, CD1d
hi
CD5
+
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.