Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization.
BACKGROUND
Androgen ablation (AA) causes apoptosis of normal and neoplastic prostate cells. It is a standard treatment for advanced prostate cancer. Androgen ablation-mediated immunological effects include bone marrow hyperplasia, thymic regeneration, T and B cell lymphopoeisis and restoration of age-related peripheral T cell dysfunction. Androgens also regulate the transcription of several cytokines. Dendritic cells (DC) are the most potent antigen presenting cells that can activate antigen-specific naïve T cells. Despite myriad clinical trials involving DC-based prostate cancer immunotherapies, the effects of AA on DC function remain largely uncharacterized. Therefore, we investigated the effects of AA on DC and whether it could improve the efficacy of prostate cancer immunotherapy.


METHODS
Cytokine expression changes due to AA were quantified by multiplex ELISA. Flow cytometry was used to assess AA-mediated effects on DC maturation and expression of costimulatory markers. Mixed leukocyte reactions and cell-mediated lysis assays elucidated the role of androgens in DC function. The effect of AA on the efficacy of vaccination against a prostate tumor-associated antigen was tested using Elispot assays.


RESULTS
Androgen ablation increased dendritic cell maturation and costimulatory marker expression, but had no effect on DC costimulatory function. However, DC isolated from castrated mice increased the expression of key cytokines by antigen-experienced T cells while decreasing their expression in naïve cells. Finally, androgen ablation improved immune responses to vaccination only when applied after immunization.


CONCLUSIONS
Androgen ablation causes differential effects of DC on primary and secondary T cell responses, thus augmenting vaccine immunogenicity only when applied after immunization.
Koh
Yi T
YT
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Gray
Andrew
A
Higgins
Sean A
SA
Hubby
Bolyn
B
Kast
W Martin
WM
D000728:Androgens / Q000276:immunology*; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology*; D007114:Immunization / Q000379:methods; D019041:L-Selectin / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D013601:T-Lymphocytes / Q000276:immunology
D000728:Androgens; D019496:Cancer Vaccines; D019041:L-Selectin