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, since 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 1a (MIP-1a, CCL3) and Fms-like tyrosine kinase-3 ligand (Flt3L) enhanced both antitumoral and antiviral immune responses. Though immune-mediated clearance of the virus can restrict therapeutic efficacy of virotherapy, MIP-1a/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-1a/FLT3L-virotherapy, we observed systemic antitumoral effects by MIP-1a/FLT3L-virotherapy on uninfected lung metastasis in immunocompetent mice, but not in nude mice. Furthermore, MIP-1a/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.