Interleukin-1 beta-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression
- 31 January 2021
- Vol. 70 (2), 330-341
- https://doi.org/10.1136/gutjnl-2019-319912
Abstract
Objective Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1 beta (IL-1 beta) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1 beta and chronic pancreatitis might contribute to PDAC progression. Design We crossed LSL-Kras(+/G12D);Pdx1-Cre (KC) mice with transgenic mice overexpressing IL-1 beta to generate KC-IL1 beta mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples. Results KC-IL1 beta mice developed PDAC with liver metastases. IL-1 beta treatment increased Kras(+/G12D) pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1 beta pancreata. Adoptive transfer of B lymphocytes from KC-IL1 beta mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1 beta mice. B cells isolated from KC-IL1 beta mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8(+) T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1 beta pancreata, and depletion of IL-35 decreased the number of PD-L1(+) B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival. Conclusion We show here that IL-1 beta promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.Keywords
Funding Information
- Japanese Society of Gastroenterology
- Mitsukoshi Health and Welfare Foundation
- Japan Society for the Promotion of Science
- Uehara Memorial Foundation
- Deutsche Forschungsgemeinschaft (DFG RE3440/1-1)
- Pancreatic Cancer Action Network
- American Association for Cancer Research
- National Institutes of Health (P30CA013696, R35CA210088, T32CA203703)
- Lustgarten Foundation
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