Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

Abstract : Replication competent vesicular stomatitis virus (VSV) can exert a dual antitumor effect by triggering direct tumor lysis and eliciting tumor specific immunity. VSV can also deliver tumor associated epitopes or other immunomodulatory molecules to enhance the antitumor immune responses. This is particularly desirable for lung tumors, which are usually poorly immunogenic, and quickly develop drug resistance. In order to examine the oncolytic effects of VSV in drug-resistant lung cancer cells, we utilized mouse lung cancer cells KLN205 (K-CP0) to generate cisplatin-resistant cells, K-CP3 and K-CP6. Two cell lines were generated by prolonged exposure to increasing concentrations of cisplatin, and both K-CP3 and K-CP6 were sensitive to the cytopathic effect of VSV. Cisplatin-resistant cells had decreased level of p-Akt and upregulated several markers of autophagy, including the scaffold protein Beclin 1 and microtubule-associated light chain protein 1. When grown subcutaneously in immunocompetent DBA/2 mice, both K-CP0 and K-CP6 formed tumors. Intratumoral injection of VSV into either K-CP0 or K-CP6 tumors led to a delay in tumor growth. Histological examination of K-CP0 and K-CP6 tumors revealed a decrease in necrotic areas in the VSV-treated tumors, and the levels of infiltrating leukocytes were similar across the VSV-treated tumors. Altogether the data indicate that VSV-based therapy is effective against a cisplatin-resistant lung tumor model.