Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand
- 669 Downloads
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.
KeywordsCD40L 5-Fluorouracil Immunotherapy Chemotherapy Urinary bladder cancer
The authors thank Berith Nilsson at Uppsala University for technical assistance with viral vector production and Marina Ioannou at IMBB-FORTH for cell culture assistance. This work was supported by the European Commission FP6 program Apotherapy (EC contract number 037344) to Aristides Eliopoulos and Angelica Loskog, the EC FP7 programmes INFLA-CARE (EC contract number 223151) and ‘Translational Potential’ (TransPOT; EC contract number 285948) to Aristides Eliopoulos, and by a Swedish Research Council grant to Angelica Loskog. Aristides Eliopoulos also acknowledges co-funding of this research by the General Secretariat of Research and Technology of Greece through the Operational Program Competitiveness and Entrepreneurship (OPC II), NSRF 2007-2013, action “SYNERGASIA 2011”, Project THERA-CAN (contract number 11ΣΥΝ_1_485).
Conflict of interest
The authors have no conflicts of interest to declare except from Angelica Loskog who is the CEO of Lokon Pharma AB, a scientific advisor at NEXTTOBE AB and has a royalty agreement with Alligator Bioscience AB.
- 19.Afford SC, Randhawa S, Eliopoulos AG, Hubscher SG, Young LS, Adams DH (1999) CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med 189:441–446PubMedCentralPubMedCrossRefGoogle Scholar
- 21.Moschonas A, Kouraki M, Knox PG, Thymiakou E, Kardassis D, Eliopoulos AG (2008) CD40 induces antigen transporter and immunoproteasome gene expression in carcinomas via the coordinated action of NF-kappaB and of NF-kappaB-mediated de novo synthesis of IRF-1. Mol Cell Biol 28:6208–6222PubMedCentralPubMedCrossRefGoogle Scholar
- 24.Vonderheide RH, Butler MO, Liu JF, Battle TE, Hirano N, Gribben JG, Frank DA, Schultze JL, Nadler LM (2001) CD40 activation of carcinoma cells increases expression of adhesion and major histocompatibility molecules but fails to induce either CD80/CD86 expression or T cell alloreactivity. Int J Oncol 19:791–798PubMedGoogle Scholar