Virus infections allow for tumor-directed DC vaccination in a mouse model of endogenously induced transgenic liver tumors

Tumor-responsive cytotoxic T-cells have great potential for curative tumor therapy. However, DC-vaccines for expansion of antitumoral T-cell responses have so far yielded limited therapeutic success in the treatment of solid cancers. For therapeutic success, breaking tumor-specific tolerance mechanisms appears mandatory before a potent tumor-specific cytotoxic T-cell response can be triggered by immunotherapeutic interventions.

In our study we identified tumor-tissue inflammation, induced by intratumoral infection with a telomerase-dependent, tumor-selectively replicating adenovirus, as an important precondition for effective DC-vaccination against a tumor-associated antigen (TAA). First investigations were carried out in syngeneic, immunocompetent mouse models with subcutaneously engrafted CMT64 or KLN205 tumors expressing ovalbumin or hemagglutinin as model TAA. Tumors received an intratumoral infection with a telomerase-dependent oncolytic adenovirus (hTert-Ad). We observed that a tumor-targeted DC-vaccine was only capable of eliciting potent antitumoral CD8 T-cell responses when administered during apparent virus-induced tumor lysis and inflammation, a regimen named 'oncolysis-assisted DC-vaccination' (ODC). In contrast, single treatments were ineffective, and importantly, the DC-vaccine was also ineffective when applied before viral lysis or after tumor tissue recovery. Interestingly, ODC-mediated T-cell response interfered with virus-specific antibody responses. Supporting the role of viral oncolysis and cross presentation of tumor-associated antigens, application of TLR-activators could not substitute for virus-induced tumor inflammation. As an essential prerequisite for treating metastases, ODC facilitated significant tumor regression and successful eradication of pre-established lung colonies. Unexpectedly, depletion of regulatory T-cells (Tregs) did not further enhance therapeutic efficacy of ODC. In contrast, antitumoral cytotoxicity was abrogated and antiviral immunoglobulins were restored. This phenomenon could be attributed to a compensatory induction of myeloid-derived suppressor cells in inflamed tumors preventing ODC-mediated immune responses.

We finally applied ODC-treatment to endogenously established transgenic liver tumors in wildtype mice. These tumors were generated by hydrodynamic injection of transposon plasmids encoding for natural oncogenes including KRasG12V and Akt in combination with sleeping beauty transposase. After tumor onset, mice where treated by ODC and tumor-specific immune T-cell immune responses were determined by antigen-specific IFNg release. We observed that ODC indeed elicited tumor-directed immune responses in this clinically relevant model of endogenously-induced transgenic tumors.

We therefore conclude that ODC is a promising approach for viro-immunotherapy of hepatic tumors.