Improvement of the cytotoxic T lymphocyte response against hepatocellular carcinoma by transduction of cancer cells with an adeno-associated virus carrying the interferon-γ gene.

Dendritic cell (DC)-based antigen-targeted immunotherapy may offer effective adjuvant therapy for hepatocellular carcinoma (HCC), in which cytotoxic T lymphocytes (CTLs) are key. However, in a number of cases, the activity of CTLs is completely inhibited due to the downregulated expression of major human leukocyte antigen (HLA) class I molecules by HCC cells. The aim of the present study was to overcome this issue. Hep3B cells were transduced by HCC-specific recombinant adeno-associated virus (rAAV) carrying human α-fetoprotein promoter (AFPp) and the interferon-γ (IFN-γ) gene (rAAV/AFPp-IFN-γ). rAAV carrying the cytomegalovirus promoter (CMVp) and human α-fetoprotein (AFP) gene (rAAV/CMVp-AFP) was used to transduce professional antigen-presenting DCs for the purpose of stimulating a CTL response. It was observed that transduction of DCs with rAAV/CMVp-AFP resulted in: (i) AFP and interleukin-12 expression; (ii) high expression levels of cluster of differentiation (CD)80, CD83, CD86, CD40, HLA-death receptor and CD1a; (iii) T cell populations with marked IFN-γ expression; (iv) a high percentage of CD69+/CD8+ T cells; and (v) the activity of CTLs against HLA-A2-expressing Hep3B cells. The transduction of Hep3B cells with rAAV/AFPp-IFN-γ resulted in: (i) IFN-γ expression; (ii) upregulated expression of HLA-A2; and (iii) an improved CTL response against HLA-A2-deficient Hep3B cells. rAAV/CMVp-AFP-transduced DCs elicited an AFP-specific and HLA-class I-restricted CTL response against Hep3B cells. In conclusion, it was shown that the transduction of Hep3B with rAAV/AFPp-IFN-γ upregulated the expression of HLA-A2 and improved the sensitivity to CTL response. [ABSTRACT FROM AUTHOR]