Proteasome inhibition during oncolytic infection improves antitumoral immunity and inhibits metastatic growth of HCC

Infection of a dying cell by a pathogen dictates the immune response against intracellular antigens, but the impact of tumor cell death during oncolytic viral infection on the induction of antitumoral immunity is unknown. Recently, ER-stress due to disruption of the unfolded-protein-response (UPR) has been implicated in the bypass of immune tolerance mechanisms. Since viruses and proteasome inhibitors both induce accumulation of misfolded proteins, we investigated ER-stress mediated apoptosis and antitumoral immune responses in mouse models of hepatocellular carcinoma after treatment with the proteasome inhibitor Bortezomib and the tumor-specifically replicating adenovirus hTert-Ad. Proteasome inhibition during hTert-Ad infection disrupted the UPR by elimination of Grp78/BiP, and by inhibition of elF2a-phosphorylation leading to significantly enhanced ER-stress-mediated apoptosis of HCC cells and improved oncolysis in HCC xenografts in immunodeficient mice. In immunocompetent HCC mouse models, Bortezomib decreased antiviral immune responses, whereas ER-stress-induced apoptosis of HCC resulted in caspase-dependent triggering of antitumoral immunity. Most important the Bortezomib/oncolytic therapy combination effectively eliminated non-infected HCC lung metastases in immunocompetent tumor models, but not in immunodeficient mice, demonstrating the systemic therapeutic efficacy of ER-stress induced antitumoral immune responses. Conclusion: Proteasome inhibition during oncolytic therapy disrupts virus-induced UPR and leads to enhanced ER-stress-induced apoptosis, improved local oncolysis and systemic antitumoral immunity in mouse tumor models. ER-stress induced apoptosis appears to be a danger signal for the immune system that should be included in immunotherapeutic strategies against tumors.

ER stress - HCC - immunotherapy - oncolytic - proteasome - virotherapy