Objective Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression.
Design We crossed LSL-Kras +/G12D;Pdx1-Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β 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-IL1β mice developed PDAC with liver metastases. IL-1β treatment increased Kras+/G12D pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1β pancreata. Adoptive transfer of B lymphocytes from KC-IL1β mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1β mice. B cells isolated from KC-IL1β 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-IL1β 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-1β 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.
- chronic pancreatitis
- pancreatic cancer
- cancer immunobiology
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RT and MM contributed equally.
Contributors RT and MM contributed equally. Conception and design of the study: RT, MM and TCW. Collection of data: RT, MM, MS, ZJ, TT, GV, BWR, RAW, YH and CBW. Analysis and interpretation of data: RT, MM, ACI, TAG and KPO. Resources: TAG, JG and KPO. Administrative support: YT. Drafting of the manuscript: RT and MM. Supervision of the manuscript: TCW. All authors read, revised and approved the final draft.
Funding TCW received grants from the NIH (R35CA210088), the Pancreatic Cancer Action Network—ACCR (Innovative Grant) and the Lustgarten Foundation. RT and TT were supported by Uehara Memorial Foundation. BWR was supported by a German Research Foundation grant (DFG RE3440/1-1). TT was supported by the Japanese Society of Gastroenterology (JSGE). RAW was supported by the medical oncology T32 grant (T32CA203703). YH was supported by a grant from the Mitsukoshi Health and Welfare Foundation and JSPS Postdoctoral Fellowships for Research Abroad. CBW was supported by a German Research Foundation (DFG) grant. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30CA013696 and used the resources of the Cancer Center Flow Core Facility.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The authors used deidentified participant data at Columbia University Medical Center.
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