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Immunity. 2018 Apr 17;48(4):773-786.e5. doi: 10.1016/j.immuni.2018.03.018. Epub 2018 Apr 3.

Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells.

Author information

1
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
2
Departments of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA.
3
MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST; School of Medicine, Tsinghua University, Beijing 100084, China.
4
Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing 100029, China.
5
MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST; School of Medicine, Tsinghua University, Beijing 100084, China; Department of Biological Sciences, Center for Systems Biology, The University of Texas, Dallas, TX 75080, USA.
6
The Campbell Family Cancer Research Institute and University Health Network, Toronto, ON M5G 2C1, Canada.
7
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing 100084, China. Electronic address: chendong@tsinghua.edu.cn.

Abstract

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

PMID:
29625896
DOI:
10.1016/j.immuni.2018.03.018
[Indexed for MEDLINE]
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