The WNT/beta-catenin signaling inhibitor XAV939 enhances the elimination of LNCaP and PC-3 prostate cancer cells by prostate cancer patient lymphocytes in vitro
Abstrakt
Upregulated Wnt/beta-catenin signaling is associated with increased cancer cell resistance and cancer cell-elicited immunosuppression. In non-neoplastic immune cells, upregulated Wnt/beta-catenin is, however, associated with either immunosuppression or immunostimulation.
Therefore, it is difficult to predict the therapeutic impact inhibitors of Wnt/beta-catenin signaling will have when combined with cancer immunotherapy. Here, we evaluated the benefit(s) of the Wnt/beta-catenin signaling inhibitor XAV939 in the in vitro elimination of LNCaP prostate cancer cells when cocultured with lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa).
We found that 5 mu M XAV939 inhibited beta-catenin translocation to the nucleus in LNCaP cells and CD4(+) BRPCa lymphocytes without affecting their proliferation and viability. Preconditioning BRPCa lymphocytes with 5 mu M XAV939 accelerated the elimination of LNCaP cells during the coculturing.
However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate LNCaP cells unless coculturing and re-coculturing were performed in the presence of 5 mu M XAV939. Comparable results were obtained for PC-3 prostate cancer cells.
These findings provide a rationale for combining cell-based immunotherapy of PCa with inhibitors of Wnt/beta-catenin signaling.