New preclinical data have shown the potential of inducing overexpression of suppressor of cytokine signalling 3 (SOCS3) in castration-resistant prostate cancer (CRPC) using gene therapy. This therapy probably works by attenuating the IL-6–Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling pathway, which is often overactivated in prostate cancer.

Credit: Pat Morgan/Springer Nature Limited

The investigators created replication-deficient, recombinant adenoviral vectors expressing human SOCS3 (Ad-hSOCS3) or mouse Socs3 (Ad-mSOCS3). Human (DU145 and PC3) and mouse (TRAMP-C2) CRPC cells were treated with their corresponding adenoviral vectors. Gene therapy induced SOCS3 overexpression in all three CRPC cell lines. Cell proliferation and expression of phosphorylated STAT3 (pSTAT3) were inhibited in DU145 and TRAMP-C2 cells by gene therapy with Ad-SOCS3. Furthermore, Ad-SOCS3 treatment induced apoptosis in these cell lines. However, Ad-hSOCS3 treatment had no effect on proliferation, pSTAT3 expression or apoptosis in PC3 cells, in which no STAT3 expression was detected.

In DU145 cells specifically, treatment with Ad-hSOCS3 suppressed expression of IL-6. G0–G1 cell cycle arrest was also induced by Ad-hSOCS3, similar to the effect on the cell cycle of suppression of STAT3 expression using small interfering RNA in these cells.

In TRAMP-C2 cells, Ad-mSOCS3 treatment decreased the expression of IFNγ-induced programmed cell death 1 ligand 1 (PD-L1) expression. However, IFNγ treatment did not increase PD-L1 expression in DU145 cells, and Ad-hSOCS3 treatment did not suppress PD-L1 expression in these cells.

Cytotoxicity assays showed that Ad-SOCS treatment considerably increased the cytotoxicity of natural killer (NK) cells in both TRAMP-C2 and DU145 cells; however, the presence of recombinant IL-6 inhibited this effect in DU145 cells.

In vivo, treatment of mice harbouring DU145 xenograft tumours with combined Ad-hSOCS3 and NK cells substantially inhibited tumour growth compared with NK cell treatment alone. Immunohistochemical analysis showed that more CD56+ cells were present in tumours from mice that received combined treatment than those that received NK cells alone.

Cell proliferation and expression of phosphorylated STAT3 … were inhibited in DU145 and TRAMP-C2 cells by gene therapy with Ad-SOCS3

These results show that treatment of CRPC cell lines with Ad-SOCS3 induces its overexpression in these cells and could increase the sensitivity of CRPC cells to NK cells. Thus, Ad-SOCS3 gene therapy plus NK cell immunotherapy has therapeutic potential in men with CRPC.