Cytokine mediated protection of human dendritic cells from prostate cancer-induced apoptosis is regulated by the Bcl-2 family of proteins

Prostate cancer is the most common cancer in men in the United States, and second in cancer-induced mortality. It is likely that tumour-induced immuno suppression is one of the reasons for low treatment efficacy in patients wi th advanced prostate cancer. It has been recently demonstrated that prostat e cancer tissue is almost devoid of dendritic cells (DC), the major antigen -presenting cells responsible for the induction of specific antitumour immu ne responses. In this study, we have tested the hypothesis that prostate ca ncer induces progressive suppression of the DC system. We found that co-inc ubation of human DC with three prostate cancer cell lines led to the high l evels of premature apoptosis of DC, which were significantly higher than in DC cultures co-incubated with normal prostate cells or blood leucocytes. S timulation of DC for 24 hours with CD40 ligand (CD154), IL-12 or IL-15 prio r to their cc-incubation with prostate cancer cells resulted in a significa nt increase in DC survival in the tumour microenvironment. Furthermore, act ivation of DC with these cytokines was also accompanied by increased expres sion of the anti-apoptotic protein Bcl-x(L) in DG, suggesting a possible me chanism involved in DC protection from apoptotic death. In summary, our dat a demonstrate that prostate cancer induces active elimination of DC in the tumour microenvironment. Stimulation of DC by CD154, IL-12 or IL-15 leads t o an increased expression of the anti-apoptotic protein Bcl-x(L) and increa sed resistance of DC to prostate cancer-induced apoptosis. These results su ggest a new mechanism of tumour escape from immune recognition and demonstr ate the cytokine-based approaches which might significantly increase the ef ficacy of DC-based therapies for cancer. (C) 2000 Cancer Research Campaign.