Immunity
Volume 48, Issue 4, 17 April 2018, Pages 773-786.e5
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Article
Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells

https://doi.org/10.1016/j.immuni.2018.03.018Get rights and content
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Highlights

  • Upregulated B7S1 expression on APCs correlates with CD8+ T dysfunction in human cancer

  • Inhibition of B7S1 promotes CD8+ T cell-mediated tumor immunity in murine cancer models

  • B7S1, via its receptor expressed on early activated CD8+ TILs, drives T cell exhaustion

  • Co-blockade of B7S1 and PD-1 can more potently reinvigorate anti-tumor responses

Summary

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.

Keywords

B7S1
tumor immunity
T cell exhaustion
Eomes
PD-1
combinational blockade of immune checkpoints

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