Li et al. show that the molecule B7S1, expressed on APCs and some tumor cells, is an inhibitory ligand which acts to suppress activated CD8+ T cells via Eomes overexpression and other pathways that largely overlap with PD-1, possibly explaining the low response rate in patients treated with PD-1 blockade. Blockade of both B7S1 and PD-1 synergistically improved the antitumor response in mice. Coexpression of PD-1 and the putative B7S1 receptor on CD8+ TILs indicated an activated, transitional state, while coexpression of PD-1 and TIM-3 was associated with exhaustion.
The molecular mechanisms whereby CD8(+) T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7-H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8(+) T cell dysfunction. B7S1 inhibition suppressed development of murine tumors. Putative B7S1 receptor was co-expressed with PD-1 but not T cell immunoglobulin and mucin-domain containing-3 (Tim-3) at an activated state of early tumor-infiltrating CD8(+) T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression. Combinatorial blockade of B7S1 and PD-1 synergistically enhanced anti-tumor immune responses. Collectively, B7S1 initiates dysfunction of tumor-infiltrating CD8(+) T cells and may be targeted for cancer immunotherapy.