Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression
Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression
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DOI：
10.1136/gutjnl-2019-319912
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发表时间：
2021-02-01
期刊：
影响因子：
24.5
通讯作者：
Wang, Timothy C.
中科院分区：
文献类型：
--
作者：
Takahashi, Ryota;Macchini, Marina;Wang, Timothy C.
目的长期慢性胰腺炎是胰腺导管腺癌（PDAC）的危险因素。白细胞介素-1 β（IL-1 β）在PDAC中与较短的生存期相关。设计我们将LSL-Kras（+/G12 D）; Pdx 1-Cre（KC）小鼠与过表达IL-1 β的转基因小鼠杂交以产生KC-IL 1 β小鼠，并纵向跟踪它们。我们使用胰腺三维体外培养来评估腺泡-导管化生的形成。免疫细胞通过流式细胞术和免疫组织化学染色进行分析。B淋巴细胞过继转移或耗竭Kras突变小鼠。结果KC-IL 1 β小鼠发生PDAC伴肝转移。IL-1 β处理增加Kras（+/G12 D）胰腺球状体形成。KC-IL 1 β胰腺组织中CXCL 13表达和B淋巴细胞浸润增加。从KC-IL 1 β小鼠连续转移B淋巴细胞促进肿瘤形成，而B细胞的耗竭阻止了KC-IL 1 β小鼠中的肿瘤进展。从KC-IL 1 β小鼠中分离的B细胞具有更高的PD-L1表达，更多的调节性B细胞，受损的CD 8（+）T细胞活性并促进肿瘤发生。IL-35在KC-IL 1 β胰腺中增加，IL-35的消耗减少了PD-L1（+）B细胞的数量。最后，在人类PDAC样品中，PDAC患者具有较高的B细胞浸润内tumors表现出显着较短的survival.Conclusion我们在这里表明，IL-1 β促进肿瘤发生的一部分，通过诱导免疫抑制B细胞的扩增。这些发现指出了B抑制细胞在胰腺肿瘤发生中的重要性。
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.