title: Antitumoral immune response by recruitment and expansion of dendritic cells in tumors infected with telomerase-dependent oncolytic viruses.
abstract: Virotherapy can potentially be used to induce tumor-specific immune responses and to overcome tumor-mediated tolerance mechanisms because apoptotic tumor cells are exposed together with viral danger signals during oncolysis. However, insufficient numbers of dendritic cells (DC) present at the site of oncolysis can limit a tumor-specific immune response and the resulting therapeutic benefit. We investigated MHC class I peptide-specific immune responses against model antigens ovalbumin (OVA) and hemagglutinin (HA) in mouse tumor models that support efficient replication of the oncolytic adenovirus hTert-Ad. Virotherapy resulted in peptide-specific cytotoxic T-cell responses against intracellular tumor antigens. Triggering of DC and T-cell infiltration to the oncolytic tumors by macrophage inflammatory protein 1alpha (MIP-1alpha, CCL3) and Fms-like tyrosine kinase-3 ligand (Flt3L) enhanced both antitumoral and antiviral immune responses. Although immune-mediated clearance of the virus can restrict therapeutic efficacy of virotherapy, MIP-1alpha/FLT3L-augmented hTert-Ad virotherapy inhibited local tumor growth more effectively than virotherapy alone. In agreement with the hypothesis that immune-mediated mechanisms account for improved outcome in MIP-1alpha/FLT3L virotherapy, we observed systemic antitumoral effects by MIP-1alpha/FLT3L virotherapy on uninfected lung metastasis in immunocompetent mice but not in nude mice. Furthermore, MIP-1alpha/FLT3L virotherapy of primary tumors was strongly synergistic with tumor DC vaccination in inhibition of established lung metastasis. Combined viroimmunotherapy resulted in long-term survival of 50% of treated animals. In summary, improvement of cross-presentation of tumor antigens by triggering of DC and T-cell infiltration during virotherapy enhances antitumoral immune response that facilitates an effective viroimmunotherapy of primary tumors and established metastases.
authors.affiliation: Department of Gastroenterology, Medical School Hannover, Hannover, Germany.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edukulla
authors.forename: Edukulla
authors.initials: E
authors.lastname: Ramakrishna
authors.forename: Norman
authors.initials: N
authors.lastname: Woller
authors.forename: Bettina
authors.initials: B
authors.lastname: Mundt
authors.forename: Sarah
authors.initials: S
authors.lastname: Knocke
authors.forename: Engin
authors.initials: E
authors.lastname: Gürlevik
authors.forename: Michael
authors.initials: M
authors.lastname: Saborowski
authors.forename: Nisar
authors.initials: N
authors.lastname: Malek
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Florian
authors.initials: F
authors.lastname: Kühnel
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
mesh_terms: D000256:Adenoviridae / Q000472:pathogenicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006388:Hemagglutinins / Q000276:immunology; D007668:Kidney; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology* / Q000821:virology*; D010047:Ovalbumin / Q000276:immunology; D019098:Telomerase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D006388:Hemagglutinins; D010047:Ovalbumin; D019098:Telomerase