| First Author | Das S | Year | 2020 |
| Journal | Cancer Res | Volume | 80 |
| Issue | 5 | Pages | 1088-1101 |
| PubMed ID | 31915130 | Mgi Jnum | J:285785 |
| Mgi Id | MGI:6393164 | Doi | 10.1158/0008-5472.CAN-19-2080 |
| Citation | Das S, et al. (2020) Tumor Cell-Derived IL1beta Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer. Cancer Res 80(5):1088-1101 |
| abstractText | 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 proinflammatory cytokine IL1beta is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell-derived IL1beta promoted the activation and secretory phenotype of quiescent pancreatic stellate cells and established an immunosuppressive milieu mediated by M2 macrophages, myeloid-derived suppressor cells, CD1d(hi)CD5(+) regulatory B cells, and Th17 cells. Loss of tumor cell-derived IL1 signaling in tumor stroma enabled intratumoral 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 IL1beta significantly enhanced the antitumor activity of alpha-PD-1 and was accompanied by increased tumor infiltration of CD8(+) T cells. Tumor cell expression of IL1beta 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 IL1beta in orchestrating an immune-modulatory program that supports pancreatic tumorigenesis. SIGNIFICANCE: These findings identify a new modality for immune evasion in PDA that depends on IL1beta production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy. |
