Dendritic cell based immunotherapy against adrenocortical carcinoma – screening for suitable targets

Objective: No effective medical therapy against adrenocortical carcinoma (ACC) is available. New promising therapeutic approaches are currently developed for a variety of cancers, such as dendritic cell (DC) based immunotherapy or targeting the tumor stroma. We are interested to clarify whether a combination of these modalities is a promising approach in patients with ACC. However, it is not known whether T-cells corresponding to stromal and adrenal specific products are present in humans. The main goal of our study was, therefore, to identify human antigens expressed in ACC, against which a T-cell response can be generated and tolerance can be overcome.

Methods: We analyzed the expression of the universal tumor stroma antigens fibroblast activation protein (FAP) and survivin in ACC. In addition, we chose 4 adrenal specific antigens namely ACTH receptor, StaR, P450scc, and P450c21. To determine whether sufficient T cell clones corresponding to these targets are present in PBMCs, we measured the ability of RNA-transfected DC to stimulate a cytotoxic T lymphocyte (CTL) response.

Results: FAP and Survivin mRNA was present in 12 of 14 ACC and the mean mRNA level was 100-times and 50-times higher than in normal adrenals (n=10). Against FAP, survivin, StAR, and P450c21 a specific CTL response could be stimulated in 6/6, 4/4, 3/4 and 3/4 donors, resp. In contrast, P450scc or ACTH-R specific CTL responses were generated only 1/4 and 0/4 individuals, respectively. To enhance the immunogenicity of the antigens, a lysosomal targeting signal derived from LAMP-1 was fused to the C-terminus of coding sequence of the antigen to redirect the translated product into the class II presentation pathway. In comparison to FAP, transfection of DC with FAP-LAMP mRNA led to significantly enhanced CD4+ and CD8+T-cell responses.

Conclusions: These findings provide first evidence that DCs transfected with antigen specific mRNA may be a promising therapeutic approach against ACC and suggest that FAP, survivin, StAR and P450c21 are suitable target antigens.