Neoadjuvant Estradiol or Androgen Deprivation in Clinically Localized Prostate Cancer

Estrogens are effective means of treating advanced prostate cancer. In randomized studies estrogens have better cancer control rates than orchiectomy alone, suggesting that estrogen efficacy is not limited to its ability to suppress testosterone. One hypothesis is that estrogens modulate immunity to prostate cancer through direct activation of effector cells and by upregulating cytokines in prostatic stroma. Administration of estrogen in murine models induces infiltration of normal prostate with T lymphocytes even in castrate male animals potentially through induction of autoimmunity to normally cryptic prostate antigens. Estrogens activate multiple immune effectors and autoimmunity in a broad variety of experimental settings, suggesting upregulation of immune recognition on many levels. Pilot data demonstrates that estrogens upregulate expression of interferon regulated genes, major histocompatibility antigens (MHC) on prostate cancer, and increase both number and activation of natural killer (NK) cells. Other groups have shown that standard forms of androgen deprivation also induce immunity against both normal and malignant prostate tissue. We propose to test the hypothesis that administration of estrogen and/or androgen deprivation induces immune recognition of prostate cancer in humans through upregulation of major histocompatibility antigens on tumor and induction of tumor specific immunity. The specificity of estrogen effect will be tested by comparing measures of immunity in patients treated with estradiol, androgen deprivation or no neoadjuvant therapy. Plan of therapy The specific aims of this proposal are: 1. To treat patients with clinically localized, low to intermediate risk prostate cancer who are candidates for radical prostatectomy with either standard androgen deprivation prior to surgery (neoadjuvant androgen deprivation) or neoadjuvant transdermal estradiol. Patients will undergo radical prostatectomy 21 days after initiation of treatment. 2. To evaluate radical prostatectomy specimens obtained from these patients for expression of MHC class I and II, and NK ligands MICA and MICB in prostate carcinoma and adjacent prostate by immunohistochemistry (IHC) and Western analysis. 3. To evaluate tumor tissue for infiltration by clonal T lymphocytes, NK cells, and plasmacytoid dendritic cells using IHC and spectratyping of T cell receptor gene rearrangements. 4. To evaluate patients for the induction of tumor specific antibodies using patient immunoglobulin collected before and after neoadjuvant therapy (SEREX) 5. To evaluate patients for induction of NK cells and upregulation of the NK receptor NKG2D on patient lymphocytes by androgen deprivation and estradiol. 6. To evaluate the effects of androgen deprivation and estradiol on induction of plasma and tissue levels of interferon gamma, alpha, beta, IL-4 and GM-CSF by ELISA and ribonuclease protection assay.