B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma

J Exp Med. 2006 Apr 17;203(4):871-81. doi: 10.1084/jem.20050930. Epub 2006 Apr 10.

Abstract

Tumor-associated macrophages are a prominent component of ovarian cancer stroma and contribute to tumor progression. B7-H4 is a recently identified B7 family molecule. We show that primary ovarian tumor cells express intracellular B7-H4, whereas a fraction of tumor macrophages expresses surface B7-H4. B7-H4+ tumor macrophages, but not primary ovarian tumor cells, suppress tumor-associated antigen-specific T cell immunity. Blocking B7-H4-, but not arginase-, inducible nitric oxide synthase or B7-H1 restored the T cell stimulating capacity of the macrophages and contributes to tumor regression in vivo. Interleukin (IL)-6 and IL-10 are found in high concentrations in the tumor microenvironment. These cytokines stimulate macrophage B7-H4 expression. In contrast, granulocyte/macrophage colony-stimulating factor and IL-4, which are limited in the tumor microenvironment, inhibit B7-H4 expression. Ectopic expression of B7-H4 makes normal macrophages suppressive. Thus, B7-H4+ tumor macrophages constitute a novel suppressor cell population in ovarian cancer. B7-H4 expression represents a critical checkpoint in determining host responses to dysfunctional cytokines in ovarian cancer. Blocking B7-H4 or depleting B7-H4+ tumor macrophages may represent novel strategies to enhance T cell tumor immunity in cancer.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / physiology
  • Antigens, Neoplasm / administration & dosage
  • Antigens, Neoplasm / immunology
  • B7-1 Antigen / biosynthesis
  • B7-1 Antigen / genetics*
  • B7-H1 Antigen
  • Biomarkers
  • Carcinoma / immunology
  • Carcinoma / metabolism*
  • Female
  • Humans
  • Immunophenotyping
  • Interleukin-10 / physiology
  • Interleukin-6 / physiology
  • Macrophages / classification
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation
  • Tumor Cells, Cultured
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1

Substances

  • Antigens, CD
  • Antigens, Neoplasm
  • B7-1 Antigen
  • B7-H1 Antigen
  • Biomarkers
  • CD274 protein, human
  • Interleukin-6
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • VTCN1 protein, human
  • Interleukin-10