Abstract
To establish optimized conditions for immunity against prostate cancer, we compared the efficacy of multiple approaches in autochthonous and s.c. transgenic adenocarcinoma of the mouse prostate (TRAMP)-based models. Mice immunized with interleukin (IL)-12-containing apoptotic, but not necrotic TRAMP-C2 cell-based, vaccines were resistant to TRAMP-C2 tumor challenge and re-challenge, independently of the route of vaccination (s.c. or i.p.). Administration of gamma-irradiated TRAMP-C2 cells preinfected with adenovirus containing both B7-1 and IL-12 genes, unlike adenovirus containing B7-1 alone, considerably protected C57BL/6 mice from TRAMP-C2 tumor growth and extended the life span of TRAMP mice. Vaccines that included dendritic cells, instead of IL-12, were equally efficient. Whereas injections of ligand-inducible caspase-1- and IL-12-containing adenoviruses cured small s.c. TRAMP-C2 tumors, nanopump-regulated delivery of viruses led to elimination of much larger tumors. The antitumor immune responses involved CD4+-, CD8+-, and natural killer cells and were strengthened by increasing the number of vaccinations. Intraprostatic administration of inducible caspase-1- and IL-12-containing adenoviruses resulted in local cell death and improved survival of adenocarcinoma-bearing TRAMP mice. Thus, tumor cell apoptosis induced by caspase in situ and accompanied by IL-12 is efficient against prostate cancer in a preclinical model.
Highlights
Due to advances in early detection and treatment of prostate cancer, the death rate from prostate cancer is at its lowest level since the National Cancer Institute began tracking cancer mortality in 1973 [1]
TRAMP-C2 cells were preinfected with AdBP1, expressing B7-1 and IL-12, and killed by one of five methods (Fig. 1A) inducing primarily apoptosis, necrosis, or both (HSV-tk/ ganciclovir treatment; refs. 9, 34)
Because inducible caspases, which can create a source of tumor antigens in situ in tumor-bearing hosts, potentially satisfy this requirement, we compared an inducible caspase–based method with several well-described approaches to induce tumor cell death
Summary
Due to advances in early detection and treatment of prostate cancer, the death rate from prostate cancer is at its lowest level since the National Cancer Institute began tracking cancer mortality in 1973 [1]. 20% to 25% of patients treated with surgery or radiation for localized prostate adenocarcinoma experience disease progression, presumably associated with occult, micrometastatic cancer. A deeper understanding is needed of the immunologic mechanisms that result in prostate cancer prevention or regression in model systems. An important question of immunotherapeutic design is whether apoptotic or necrotic tumor cells are better as a source of tumor antigens to stimulate specific antitumor immunity. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Dendritic cells are 1,000 to 10,000 times more efficient at forming MHC-peptide complexes from phagocytosed cells than at forming them from
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