PT  - JOURNAL ARTICLE
AU  - Ryota Takahashi
AU  - Marina Macchini
AU  - Masaki Sunagawa
AU  - Zhengyu Jiang
AU  - Takayuki Tanaka
AU  - Giovanni Valenti
AU  - Bernhard W Renz
AU  - Ruth A White
AU  - Yoku Hayakawa
AU  - C Benedikt Westphalen
AU  - Yagnesh Tailor
AU  - Alina C Iuga
AU  - Tamas A Gonda
AU  - Jeanine Genkinger
AU  - Kenneth P Olive
AU  - Timothy C Wang
TI  - Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte–mediated immune suppression
AID  - 10.1136/gutjnl-2019-319912
DP  - 2021 Feb 01
TA  - Gut
PG  - 330--341
VI  - 70
IP  - 2
4099  - http://gut.bmj.com/content/70/2/330.short
4100  - http://gut.bmj.com/content/70/2/330.full
SO  - Gut2021 Feb 01; 70
AB  - 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.