Induced expression of B7-H4 on the surface of lung cancer cell by the tumor-associated macrophages: a potential mechanism of immune escape

Cancer Lett. 2012 Apr 1;317(1):99-105. doi: 10.1016/j.canlet.2011.11.017. Epub 2011 Nov 20.

Abstract

B7-homolog 4 (B7-H4), a recently identified homolog of B7.1/2 (CD80/86), has been described to exert co-stimulatory and immune regulatory functions. We investigated the expression and the functional activity of B7-H4 in lung cancer in vitro and in vivo. Although a lung cancer cell line constitutively expressed B7-H4 mRNA and protein in plasma, primary tumor cell isolated from the transplanted lung carcinoma model expressed B7-H4 on the surface. Interestingly, in transplanted lung carcinoma model, the expression of membrane-bound B7-H4 in tumor cells was increased as prolonging of tumor transformation. Exposure to tumor-associated macrophages strongly induced membrane-bound B7-H4 expression on the lung cancer cell line. To elucidate the functional significance of lung cancer-related B7-H4 expression, we performed co-culture experiments of lung cancer cell with allo-reactive T cells. Lung cancer-related B7-H4 was identified as a strong inhibitor of T-cell effect. Furthermore, B7-H4 mAb had an ability to inhibit tumor growth in vivo. B7-H4 expression may thus significantly influence the outcome of T-cell tumor cell interactions and TAM induced membrane-bound B7-H4 on the lung cancer cell represents a novel mechanism by which lung cancer cells evade immune recognition and destruction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / immunology*
  • Carcinoma, Lewis Lung / pathology
  • Cell Line, Tumor
  • Coculture Techniques
  • Culture Media, Conditioned / metabolism
  • Cytotoxicity, Immunologic
  • Female
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Escape* / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / antagonists & inhibitors
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / genetics
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / metabolism*

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Culture Media, Conditioned
  • IL10 protein, mouse
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Vtcn1 protein, mouse
  • Interleukin-10
  • Interferon-gamma