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 immunosuppression is one of the reasons for low treatment efficacy in patients with advanced prostate cancer. It has been recently demonstrated that prostate cancer tissue is almost devoid of dendritic cells (DC), the major antigen-presenting cells responsible for the induction of specific antitumour immune responses. In this study, we have tested the hypothesis that prostate cancer induces progressive suppression of the DC system. We found that co-incubation of human DC with three prostate cancer cell lines led to the high levels of premature apoptosis of DC, which were significantly higher than in DC cultures co-incubated with normal prostate cells or blood leucocytes. Stimulation of DC for 24 hours with CD40 ligand (CD154), IL-12 or IL-15 prior to their co-incubation with prostate cancer cells resulted in a significant increase in DC survival in the tumour microenvironment. Furthermore, activation of DC with these cytokines was also accompanied by increased expression of the anti-apoptotic protein Bcl-x(L) in DC, suggesting a possible mechanism involved in DC protection from apoptotic death. In summary, our data demonstrate that prostate cancer induces active elimination of DC in the tumour microenvironment. Stimulation of DC by CD154, IL-12 or IL-15 leads to an increased expression of the anti-apoptotic protein Bcl-x(L) and increased resistance of DC to prostate cancer-induced apoptosis. These results suggest a new mechanism of tumour escape from immune recognition and demonstrate the cytokine-based approaches which might significantly increase the efficacy of DC-based therapies for cancer.
Pirtskhalaishvili
G
G
Department of Urology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, PA 15213, USA.
Shurin
G V
GV
Esche
C
C
Cai
Q
Q
Salup
R R
RR
Bykovskaia
S N
SN
Lotze
M T
MT
Shurin
M R
MR
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology; D023201:CD40 Ligand; D002450:Cell Communication / Q000502:physiology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000502:physiology*; D015848:Interleukin-5 / Q000096:biosynthesis / Q000502:physiology*; D007739:L Cells; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019013:CD40 Antigens; D007376:Interleukin-2; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D023201:CD40 Ligand