Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAV as oncolytic agents to kill human PDA cell lines. Receptor characterization confirmed that human PDA cell lines expressed both the alpha-2,3 and alpha-2,6-linked glycan receptors for avian and human IAVs, respectively. Consistent with this finding, PDA cell lines were sensitive to infection by human and avian IAV isolates. Growth kinetic experiments showed preferential virus replication in PDA cells over a non-transformed pancreatic ductal cell line. Finally, at early time points post treatment, infection with IAVs caused higher levels of apoptosis in PDA cells compared to gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in the non-transformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a low pathogenic avian IAV significantly inhibited tumour growth following intratumoural injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas.

IMPORTANCE:

Despite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers . In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These results suggest that low pathogenic IAVs may prove to be effective for oncolytic virotherapy of PDA, and provide grounds for further studies to develop specific and targeted viruses with the aim of testing their efficacy in clinical contexts.