Abstract
Prostate stem cell antigen (PSCA) is an attractive antigen to target using therapeutic vaccines because of its overexpression in prostate cancer, especially in metastatic tissues, and its limited expression in other organs. Our studies offer the first evidence that a PSCA-based vaccine can induce long-term protection against prostate cancer development in prostate cancer-prone transgenic adenocarcinoma mouse prostate (TRAMP) mice. Eight-week-old TRAMP mice displaying prostate intraepithelial neoplasia were vaccinated with a heterologous prime/boost strategy consisting of gene gun-delivered PSCA-cDNA followed by Venezuelan equine encephalitis virus replicons encoding PSCA. Our results show the induction of an immune response against a newly defined PSCA epitope that is mediated primarily by CD8 T cells. The prostates of PSCA-vaccinated mice were infiltrated by CD4-positive, CD8-positive, CD11b-positive, and CD11c-positive cells. Vaccination induced MHC class I expression and cytokine production [IFN-gamma, tumor necrosis factor-alpha, interleukin 2 (IL-2), IL-4, and IL-5] within prostate tumors. This tumor microenvironment correlated with low Gleason scores and weak PSCA staining on tumor cells present in hyperplastic zones and in areas that contained focal and well-differentiated adenocarcinomas. PSCA-vaccinated TRAMP mice had a 90% survival rate at 12 months of age. In contrast, all control mice had succumbed to prostate cancer or had heavy tumor loads. Crucially, this long-term protective immune response was not associated with any measurable induction of autoimmunity. The possibility of inducing long-term protection against prostate cancer by vaccination at the earliest signs of its development has the potential to cause a dramatic paradigm shift in the treatment of this disease.
Highlights
Prostate cancer is the most commonly diagnosed malignancy in the western world and is the second leading cause of cancerrelated death in American men [1]
Nineteen of 25 mice vaccinated with mPSCA DNA and boosted with mPSCA-Venezuelan Equine Encephalitis replicon particle (VRP) remained tumor-free 52 days after challenge with transgenic adenocarcinoma mouse prostate (TRAMP)-C2 murine prostate tumor cells
The tumors of the six mPSCA-vaccinated mice that developed tumors were statistically significantly smaller than the tumors of control mice vaccinated with empty-vector DNA and boosted with GFP-VRP
Summary
Prostate cancer is the most commonly diagnosed malignancy in the western world and is the second leading cause of cancerrelated death in American men [1]. Therapeutic options for advanced and metastatic prostate cancer are limited [2,3,4]. Immunotherapy is a promising prospective new treatment for this disease. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Prostate cancer immunotherapy involves the use of antigenpresenting cells that present prostate cancer–associated antigenic peptides. 5), six-transmembrane epithelial antigen of the prostate [6], prostate stem cell antigen 8), and prostatic acid phosphatase [9] The targeted antigens include prostate-specific antigen (PSA; ref. 5), six-transmembrane epithelial antigen of the prostate [6], prostate stem cell antigen (PSCA; ref. 7), prostatespecific membrane antigen (PSMA; ref. 8), and prostatic acid phosphatase [9]
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