Structure and cancer immunotherapy of the B7 family member B7x

Cell Rep. 2014 Nov 6;9(3):1089-98. doi: 10.1016/j.celrep.2014.09.053. Epub 2014 Oct 30.

Abstract

B7x (B7-H4 or B7S1) is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV) domain at 1.59 Å resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7x-expressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / pharmacology
  • Antibody-Dependent Cell Cytotoxicity / drug effects
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Epitope Mapping
  • Epitopes / chemistry
  • Epitopes / immunology
  • Humans
  • Immunosuppression
  • Immunotherapy*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice, Inbred BALB C
  • Models, Molecular
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Surface Plasmon Resonance
  • Survival Analysis
  • T-Lymphocytes / immunology
  • Tumor Microenvironment / drug effects
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / chemistry*
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / immunology*
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / metabolism

Substances

  • Antibodies, Monoclonal
  • Epitopes
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1

Associated data

  • PDB/4GOS