Circulating exosomes from esophageal squamous cell carcinoma mediate the generation of B10 and PD‐1^high Breg cells

Abstract

As one of the most frequently diagnosed cancers, esophageal squamous cell carcinoma (ESCC) remains the leading cause of malignancy‐related death worldwide. Many studies have focused on the potential role of cancer cells in educating B cells during cancer progression. Here, we aim to explore the role of circulating exosomes from ESCC in the generation of two main regulatory B (Breg) subsets, including interleukin‐10+ Bregs (B10) and programmed cell death (PD)‐1high Bregs. Firstly, we observed an elevated percentage of B10 cells in peripheral blood of ESCC patients compared with healthy controls. Then we isolated and characterized exosomes from the peripheral blood of ESCC patients and an ESCC cell line. Exosomes from ESCC patients and the ESCC cell line suppressed the proliferation of B cells and induced the augmentation of B10 and PD‐1high Breg cells. By comparing the long non‐coding RNA and mRNA expression profiles in exosomes from ESCC patients or healthy controls, we identified a series of differentially expressed genes. Finally, we undertook gene annotation and pathway enrichment analyses on differentially expressed genes to explore the potential mechanism underlying the modulatory role of cancer exosomes in B cells. Our findings contribute to the study on B cell‐mediated ESCC immunosuppression and shed light on the possible application of exosomes in anticancer therapies.

Circulating Exosomes Inhibit B Cell Proliferation and Activity

“…In contrast to our findings, Mao et al reported no changes in B cell proliferation after co-culture with plasma-derived exosomes from healthy individuals [ 19 ]. These differences might be due to different experimental conditions.…”

“…Subsets of PD-1 high Breg have been described in hepatocellular carcinoma and thyroid cancer patients [ 18 , 21 , 22 ]. Mao et al described no alteration of PD-1 levels on Breg after treatment with NC exosomes [ 19 ]. The possible reasons for this discrepancy were addressed above.…”

“…Regarding the effects of TEX on B cells, studies of hepatocellular carcinoma have shown that Breg are induced in the TME by factors, which could not be further identified [ 18 ]. Other groups demonstrated that Breg could be induced by exosomes purified from hepatocellular carcinoma cell culture supernatants or blood plasma of esophageal cancer patients [ 19 , 20 ]. To our knowledge, there is no evidence so far on the effect of HNSCC-derived TEX on B cells.…”

Comprehensive insights into the effects and regulatory mechanisms of immune cells expressing programmed death-1/programmed death ligand 1 in solid tumors

“…Notably, IL-4-induced STAT6 activation completely eliminates BCL6-mediated PD-1 upregulation of B cells, although it did not affect BCL6 14 . Consistent with these results, circulating exosomes from cancer patients enhance PD-1 expression in CD19 + B cells in ESCC 75 . Using bioinformatics technology, their analysis showed that the TLR/MAPK pathway plays a key role in regulating the transformation of PD-1 hi Breg 75 .…”

“…Consistent with these results, circulating exosomes from cancer patients enhance PD-1 expression in CD19 + B cells in ESCC 75 . Using bioinformatics technology, their analysis showed that the TLR/MAPK pathway plays a key role in regulating the transformation of PD-1 hi Breg 75 .…”