Androgen ablation augments human HLA2.1-restricted T cell responses to PSA self-antigen in transgenic mice.
BACKGROUND
In recent years, there has been an increasing interest in targeting human prostate tumor-associated antigens (TAAs) for prostate cancer immunotherapy as an alternative to other therapeutic modalities. However, immunologic tolerance to TAA poses a significant obstacle to effective, TAA-targeted immunotherapy. We sought to investigate whether androgen deprivation would result in circumventing immune tolerance to prostate TAA by impacting CD8 cell responses.


METHODS
To this end, we generated a transgenic mouse that expresses the human prostate-specific antigen (PSA) specifically in the prostate, and crossed it to the HLA-A2.1 transgenic mouse to evaluate how androgen deprivation affects human HLA A2.1-resticted T cell responses following immunization of PSA-expressing mice by vaccinia-PSA (PROSTVAC).


RESULTS
Our PSA transgenic mouse showed restricted expression of PSA in the prostate and detectable circulating PSA levels. Additionally, PSA expression was androgen-dependent with reduced PSA expression in the prostate within 1 week of castration, and undetectable PSA by day 42 after castration as evaluated by ELISA. Castration of the PSA/A2.1 hybrid mouse prior to immunization with a PSA-expressing recombinant vaccinia virus resulted in a significant augmentation of PSA-specific cytotoxic lymphocytes.


CONCLUSIONS
This humanized hybrid mouse model provides a well-defined system to gain additional insight into the mechanisms of immune tolerance to PSA and to test novel strategies aiming at circumventing immune tolerance to PSA and other TAA for targeted prostate cancer immunotherapy.
Arredouani
Mohamed S
MS
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Tseng-Rogenski
Stephanie S
SS
Hollenbeck
Brent K
BK
Escara-Wilke
June
J
Leander
Karen R
KR
Defeo-Jones
Deborah
D
Hwang
Clara
C
Sanda
Martin G
MG
D000728:Androgens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007114:Immunization; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009919:Orchiectomy; D011467:Prostate / Q000276:immunology* / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000728:Androgens; D001324:Autoantigens; D015789:HLA-A2 Antigen; D007371:Interferon-gamma; D017430:Prostate-Specific Antigen