B cells often constitute abundant cellular components in human tumors. Regulatory B cells that are functionally defined by their ability to produce IL10 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-1^hi B cells exhibited a unique CD5^hiCD24^−/+CD27^hi/+CD38^dim phenotype different from the phenotype of conventional CD24^hiCD38^hi peripheral regulatory B cells. TLR4-mediated BCL6 upregulation was crucial for PD-1^hi B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1⁺ cells or undergoing PD-1 triggering, PD-1^hi B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals. Our findings provide significant new insights for human cancer immunosuppression and anticancer therapies regarding PD-1/PD-L1.

Significance: We identify a novel protumorigenic PD-1^hi B-cell subset in human HCC that exhibits a phenotype distinct from that of peripheral regulatory B cells. TLR4-mediated BCL6 upregulation is critical for induction of PD-1^hi B cells, which operate via IL10-dependent pathways upon interacting with PD-L1 to cause T-cell dysfunction and foster disease progression. Cancer Discov; 6(5); 546–59. ©2016 AACR.

See related commentary by Ren et al., p. 477.

This article is highlighted in the In This Issue feature, p. 461