title: Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand.
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.
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Liljenfeldt
authors.forename: Katerina
authors.initials: K
authors.lastname: Gkirtzimanaki
authors.forename: Dimitra
authors.initials: D
authors.lastname: Vyrla
authors.forename: Emma
authors.initials: E
authors.lastname: Svensson
authors.forename: Angelica Si
authors.initials: AS
authors.lastname: Loskog
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000628:therapy*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D053222:Fas Ligand Protein; D011994:Recombinant Proteins; D019014:fas Receptor; D023201:CD40 Ligand; D005472:Fluorouracil