Contribution of CD95 ligand-induced neutrophil infiltration to the bystander effect in p53 gene therapy for human cancer

J Immunol. 2000 Nov 15;165(10):5884-90. doi: 10.4049/jimmunol.165.10.5884.

Abstract

Clinical trials of adenoviral p53 gene therapy provide the evidence that the bystander effect induced by the wild-type p53 gene transfer on adjacent tumor cells contributes to tumor progression; its mechanism, however, remains uncharacterized. We report in this work that injection of adenovirus expressing the human wild-type p53 gene (Ad5CMVp53) into established human colorectal tumors in nu/nu mice resulted in CD95 ligand (CD95L) overexpression, followed by a massive neutrophil infiltration. Culture supernatants of human colorectal cancer cells infected with Ad5CMVp53 exhibited a potent chemotactic activity against murine polymorphonuclear neutrophils, which could be abolished by the anti-CD95L mAb (NOK-1). In vivo cell depletion experiments indicated that neutrophils were in part responsible for the antitumor effect of the Ad5CMVp53 infection. Our data directly suggest that overexpression of CD95L by the wild-type p53 gene transfer induces neutrophil infiltration into human colorectal tumors, which may play a critical role in the bystander effect of p53 gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviruses, Human / genetics
  • Adenoviruses, Human / immunology
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / immunology
  • Cell Line, Transformed
  • Chemotaxis, Leukocyte / immunology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / therapy*
  • Cytomegalovirus / genetics
  • Cytomegalovirus / immunology
  • Fas Ligand Protein
  • Female
  • Genes, p53 / immunology*
  • Genetic Therapy* / methods
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / immunology
  • Growth Inhibitors / administration & dosage
  • Growth Inhibitors / genetics
  • Growth Inhibitors / immunology
  • Humans
  • Immunohistochemistry
  • Injections, Intralesional
  • Injections, Subcutaneous
  • Ligands
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Neutrophil Infiltration / genetics
  • Neutrophil Infiltration / immunology*
  • Tumor Cells, Cultured
  • fas Receptor / metabolism*

Substances

  • Antineoplastic Agents
  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Growth Inhibitors
  • Ligands
  • Membrane Glycoproteins
  • fas Receptor