Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand

Cancer Immunol Immunother. 2014 Mar;63(3):273-82. doi: 10.1007/s00262-013-1507-6. Epub 2013 Dec 20.

Abstract

Bystander immune activation by chemotherapy has recently gained extensive interest and provided support for the clinical use of chemotherapeutic agents in combination with immune enhancers. The CD40 ligand (CD40L; CD154) is a potent regulator of the anti-tumor immune response and recombinant adenovirus (RAd)-mediated CD40L gene therapy has been effective in various cancer models and in man. In this study we have assessed the combined effect of local RAd-CD40L and 5-fluorouracil (5-FU) administration on a syngeneic MB49 mouse bladder tumor model. Whereas MB49 cells implanted into immunocompetent mice responded poorly to RAd-CD40L or 5-FU alone, administration of both agents dramatically decreased tumor growth, increased survival of the mice and induced systemic MB49-specific immunity. This combination treatment was ineffective in athymic nude mice, highlighting an important role for T cell mediated anti-tumor immunity for full efficacy. 5-FU up-regulated the expression of Fas and immunogenic cell death markers in MB49 cells and cytotoxic T lymphocytes from mice receiving RAd-CD40L immunotherapy efficiently lysed 5-FU treated MB49 cells in a Fas ligand-dependent manner. Furthermore, local RAd-CD40L and 5-FU administration induced a shift of myeloid-derived suppressor cell phenotype into a less suppressive population. Collectively, these data suggest that RAd-CD40L gene therapy is a promising adjuvant treatment to 5-FU for the management of bladder cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Animals
  • Antibody Formation / drug effects
  • Antibody Formation / genetics
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • CD40 Ligand / genetics
  • CD40 Ligand / metabolism*
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / genetics
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Fas Ligand Protein / metabolism
  • Female
  • Fluorouracil / administration & dosage*
  • Humans
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / therapy*
  • fas Receptor / metabolism

Substances

  • Antimetabolites, Antineoplastic
  • Fas Ligand Protein
  • Recombinant Proteins
  • fas Receptor
  • CD40 Ligand
  • Fluorouracil