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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / pathology
  • Disease Models, Animal
  • Humans
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / immunology*
  • T-Box Domain Proteins / metabolism
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / genetics
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / metabolism*

Substances

  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Eomes protein, mouse
  • T-Box Domain Proteins
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Vtcn1 protein, mouse