Characterization of B cell‐mediated PD‐1/PD‐L1 interaction in pancreatic cancer patients

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a common type of pancreatic cancer with one of the worst survival rate of all malignancies. Recent studies have identified that immunosuppressive B cells could employ the PD‐1/PD‐L1 pathway to suppress antitumour T cell responses; hence, we examined the expression and function of PD‐L1 in B cells. We found that the PD‐L1 expression was significantly enriched in tumour‐infiltrating (TI) B cells than in peripheral blood (PB) B cells from the same patients. Additionally, the PB B cells from stage III and stage IV PDAC patients presented significantly higher PD‐L1 than the PB B cells from healthy controls. High PD‐L1 expression in PB B cells could be achieved by stimulation via CpG and less effectively via anti‐BCR plus CD40L, but not by coculture with pancreatic cancer cell lines in vitro. Also, STAT1 and STAT3 inhibition significantly suppressed PD‐L1 upregulation in stimulated B cells. CpG‐stimulated PB B cells could inhibit the IFN‐γ expression and proliferation of CD8 T cells in a PD‐L1‐dependent manner. Also, TI CD8 T cells incubated with whole TI B cells presented significantly lower IFN‐γ expression and lower proliferation, than TI CD8 T cells incubated with PD‐L1+ cell‐depleted TI B cells, suggesting that PD‐L1+ B cells could also suppress CD8 T cells in the tumour. Overall, this study identified that B cells could suppress CD8 T cells via PD‐L1 expression, indicating a novel pathway of immuno‐regulation in pancreatic cancer.

B-Lymphocytes in the Pathophysiology of Pancreatic Adenocarcinoma

“…PD-L1 is overexpressed in several solid human cancers, including PDAC, and represents an established mechanisms exploited by neoplastic cells to promote tumor escape from immune-surveillance ( 134 , 135 ). B-regulatory cells from patients with PDAC also express high levels of PD-L1 and in vitro interact with PD-1 expressing CD8 + T cells leading to reduced proliferation and IFN-γ secretion ( 131 , 136 ) ( Figure 2 ). Combined inhibition of IL-18 and PD-L1/PD-1 pathways with synthetic inhibitors reduces PDAC growth and metastasis formation in orthotopic animal models, reinforcing the in vivo relevance of the crosstalk between Breg and cancer cells for the progression of pancreatic cancer ( 130 ).…”

The immunoregulation effect of tumor microenvironment in pancreatic ductal adenocarcinoma

“…In human PDAC samples, PDAC patients with higher B cell content in TME have significantly shorter survival ( 96 ). When constructing mouse models, we found that during this process, extensive infiltration of Bregs increased the expression of IL-1β and decreased the activity of CD8+ T cells, promoting tumorigenesis ( 97 ), while reverse expression of PD-L1 and IL-35 in Bregs supported immune escape of tumor cells ( 98 , 99 ). In addition, one of the characteristics of the occurrence and progression of PDAC is matrix reaction.…”

The heterogeneity of CAFs and immune cell populations in the tumor microenvironment of pancreatic adenocarcinoma

“…Recent work shows that B cells can be found in two main locations in PDAC [80] : 1-scattered infiltrating the tumor-stromal surface and 2-organized in ectopic lymph-node like structures called tertiary lymphoid tissue (TLT) [80] . After affinity maturation of CD20 + naïve B cells in the germinal centers of TLT, circulating plasmablasts are produced [81] . Those plasmablasts have been shown to be the most potent subset of B cells to stimulate collagen production by CAFs, and they show high expression of genes involved in fibroblast activation and proliferation, including the collagen genes COL1A1 and COL1A2, insulin-like growth factor-1 (IGF-1), and lysyl oxidase homolog 2 (LOXL2) [81] .…”

“…After affinity maturation of CD20 + naïve B cells in the germinal centers of TLT, circulating plasmablasts are produced [81] . Those plasmablasts have been shown to be the most potent subset of B cells to stimulate collagen production by CAFs, and they show high expression of genes involved in fibroblast activation and proliferation, including the collagen genes COL1A1 and COL1A2, insulin-like growth factor-1 (IGF-1), and lysyl oxidase homolog 2 (LOXL2) [81] . A high density of B cells in TLT is associated with improved survival [80] .…”