B cells consistently represent abundant cellular components in human tumors. Regulatory B cells that are functionally defined by their ability to produce IL-10 downregulate inflammation and control T cell immunity. Here we identified a protumorigenic subset of B cells that constitutively expressed higher levels of programmed cell death-1 (PD-1) and constituted ~10% of all B cells in advanced stage hepatocellular carcinoma (HCC). These PD-1high B cells exhibited a unique CD5highCD24−/+CD27high/+CD38dim phenotype different from the phenotype of conventional CD24highCD38high peripheral regulatory B cells. TLR4-mediated Bcl-6 upregulation was crucial for PD-1high B cell induction by HCC environmental factors, and that effect was abolished by IL-4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1+ cells or undergoing PD-1 triggering, PD-1high B cells acquired regulatory functions that suppressed tumor-specific T cell immunity and promoted cancer growth via IL-10 signals. Our findings provide significant new insights for human cancer immunosuppression and anticancer therapies regarding PD-1/PD-L1.
- Received November 30, 2015.
- Revision received February 23, 2016.
- Accepted February 23, 2016.
- ©2015 American Association for Cancer Research.