Self-complementary adeno-associated virus 5-mediated gene transduction of a novel CD40L mutant confers direct antitumor effects in lung carcinoma.

Abstract

CD40 ligand (CD40L) gene therapy offers a potentially useful option for lung cancer due to its multiple antitumor activities. However, membrane-bound CD40L may be proteolytically cleaved to form soluble CD40L (sCD40L), which results in adverse effects. In a previous study by our group, it was demonstrated that recombinant self-complementary adeno-associated virus 5 (scAAV5) efficiently delivered genes to lung cancer cells. In the present study, an scAAV5 expressing a non-cleavable human CD40L mutant (scAAV5-CD40L-M) was generated and its direct antitumor effects in lung cancer were evaluated. Transduction with scAAV5-CD40L-M resulted in effective expression of CD40L on the cell surface with low levels of cleaved sCD40L, which significantly reduced the percentage of viable cells and promoted caspase-3-dependent apoptosis of CD40-positive lung carcinoma A549 cells, compared with scAAV5-CD40L transduction (P<0.05). Furthermore, treatment with scAAV5-CD40L-M exerted a significant antitumor effect against CD40-positive A549 xenografts by inducing apoptosis (P<0.05) with few side effects. Gene therapy using an scAAV5 vector expressing non-cleavable human CD40L mutant may therefore have direct antitumor effects against CD40-positive lung cancers. These tumoricidal effects of scAAV5-CD40L-M treatment make it a promising therapeutic technique for the treatment of lung cancer.