Effects of Androgen Ablation on Anti-Tumor Immunity

Abstract

Public reporting burden for this collection of infometion is estimated to average 1 hour per response, including the tine for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of infbtmation. Androgen ablation (AA) constitutes the most common therapy for the treatment of advanced prostate Ceuicer.' While initially effective at reducing tumor burden, most patients recur with androgen insensitive disease. There exists a clear need to augment the clinical efficacy of hormone-based therapies, and imraunotherapy of prostate cancer represents a promising approach for achieving such augmentation. Moreover, our data indicate that AA affects the immune system both systemically as well as at the prostate. Castration of mice stimulates B and T lymphopoiesis, thymic and bone marrow hyperplasia. The induction of apoptotic cell death following androgen ablation is accompanied by an inflammatory infiltrate comprised predominantly of activated T cells. This AA induced autoimmune-like response exerts limited anti-tumor activity in a mouse prostate cancel model, but the anti-tumor effect is potentially synergistic with CTIiA-4 blockade, which promotes the development of autoreactive T cells. We have used the first year of this proposal to obtain and produce all necessary reagents (genes, tumor cell lines, hybridomas, purified antibodies) to position ourselves for studying the effects of AA on prostate cancer immunity as these effecs might significsmtly influence the ability of a tumor-bearing host to moxint an effective immune response. SUBJECT TERMS Page 4 IntroductionNormal and cancerous prostate cells require male sex hormones (androgens) for growth. Consequently, a common treatment for prostate cancer is androgen ablation (AA) therapy. Although AA constitutes an effective means for significantly reducing tumor burden and inducing a phase of remission of tumor growth in prostate cancer, a majority of treated patients recur with untreatable, androgen insensitive tumors. Consequently, there is a need for the development of new therapies that target prostate cancer cells via mechanisms that do not rely on the hormonal sensitivity of the cells. Yet the effectiveness of AA in reducing initial tumor burden makes its continued use likely, so new therapeutic approaches that provide synergistic anti-tumor effects when combined with AA would be attractive.Considerable interest has been directed recently toward the development of immimotherapeutic approaches for the treatment of malignancy, including prostate cancer. However, it is well established that sex hormones are potent regulators of the immune response and lymphocyte development. Since immune-based therapies will likely be administered in patients imdergoing AA therapy, the loss of androgen effects may influence the nature of the host immune response. In general, androgens suppress the immune response and, conversely, castration of mice increases their ability to reject transplanted t...