Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte–mediated immune suppression

Abstract

ObjectiveLong-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.DesignWe 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.ResultsKC-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.ConclusionWe 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.

Interleukin-1β and Cancer

“…IL-1RA or NLRP3 inhibition reverses the effects of KRAS mutation on myeloproliferation [ 108 ]. Moreover, overexpression of IL-1β in KRAS G12D mutant mice accelerates the development of PDAC through autocrine activation of IL-1R1-mediated epithelial cell proliferation and an increased level of immunosuppressive PD-L1 + B-cells [ 109 ]. This finding is correlated with the fact that myeloid-derived IL-1β induces NF-κB activation more importantly in KRAS mutant (G12C or G13R) cancer cells than in WT cells, leading to drug resistance [ 110 ].…”

Identification of potential biomarkers of peripheral blood mononuclear cell in hepatocellular carcinoma using bioinformatic analysis

“…It participates in the induction process of the malignant transformation of human normal cells and plays an essential role in the control of migratory and invasive properties by promoting tumor angiogenesis and cell adhesion and by increasing cancer metastasis in a number of cancer types. [ 27 , 28 ] IL1B was reportedly upregulated in multiple types of human tumors, such as lung adenocarcinoma, [ 29 ] pancreatic ductal adenocarcinoma, [ 30 ] and HCC. [ 31 ] and served as a useful prognostic factor in different human tumors.…”

Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma

“…Pancreatic tumor cell production of inflammatory IL-1β activates CAFs to produce IL-6, CCL2 and CCL5 that polarize immunosuppressive TAMs ( 101 ). IL-1β stimulation of tumor cells upregulate CXCL13 expression and recruit PD-L1+ regulatory B cells (Bregs) ( 102 ). IL-1β blockade combined with anti-PD-1 reduced orthotopic tumor weight and improved CD8 T cell infiltration ( 101 ).…”

“…IL-1β blockade combined with anti-PD-1 reduced orthotopic tumor weight and improved CD8 T cell infiltration ( 101 ). Knockdown of IL-1β decreased tumor growth and reversed TAM immune suppression while increasing the frequency of polyclonal CD8 T cells and their production of IFNγ and Granzyme B ( 101 , 102 ). CAF production of CXCL12 also interferes with CD8 T cell infiltration ( 50 , 101 ), supporting a stromal trapping mechanism.…”

“…In both PDA patients and mouse models, B cell production of IL-35 correlated with reduced T cell tumor infiltration and increased Tregs ( 90 , 134 ). Interfering with IL-35 increased T cell infiltration and cytokine production while reducing tumor weight and PanIN lesion formation ( 90 , 102 , 134 ). IL-35 neutralization in combination with anti-PD-1 improved mouse survival while increasing intratumoral CD8 T cells and IFNγ in PDA mouse models ( 134 ).…”