Eugene D. Kwon

T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer

Manipulations capable of breaking host tolerance to induce tissue-specific T cell-mediated inflammation are of central importance to tumor immunotherapy and our understanding of autoimmunity. We demonstrate that androgen ablative therapy induces profuse T cell infiltration of benign glands and tumors in human prostates. T cell infiltration is readily apparent after 7–28 days of therapy and is comprised predominantly of a response by CD4+ T cells and comparatively fewer CD8+ T cells. Also, T cells within the treated prostate exhibit restricted TCR Vβ gene usage, consistent with a local oligoclonal response. Recruitment/activation of antigen-presenting cells in treated prostate tissues may contribute to local T cell activation. The induction of T cell infiltration in prostate tissues treated with androgen ablation may have implications for the immunotherapeutic treatment of prostate cancer as well as other hormone-sensitive malignancies, including breast carcinoma.

Carbonic Anhydrase IX Is Not an Independent Predictor of Outcome for Patients With Clear Cell Renal Cell Carcinoma

PURPOSEnExpression of carbonic anhydrase IX (CAIX) has been reported to be an independent predictor of outcome and is being investigated as a therapeutic target for patients with clear cell renal cell carcinoma (ccRCC). We attempted to validate the prognostic utility of CAIX expression using a large cohort of ccRCC patients with long-term follow-up.nnnPATIENTS AND METHODSnWe identified 730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999. Anti-CAIX monoclonal antibody (clone M75) was used, and tumor specimens were blindly scored for expression levels. Associations of CAIX expression with RCC death were evaluated using Cox proportional hazards regression models.nnnRESULTSnThere were 241 RCC deaths and a median of 9.4 years of follow-up for patients still under observation. CAIX was expressed in 708 (97.0%) of the specimens; 163 tumors (22.3%) exhibited low ( 85% tumor cells positive) expression, and 567 (77.7%) exhibited high (> 85% tumor cells positive) expression. Univariately, low CAIX expression was associated with increased risk of RCC death relative to high expression (risk ratio = 1.65; P < .001). However, low CAIX expression was not associated with RCC death after adjusting for nuclear grade or coagulative tumor necrosis. Additionally, we observed CAIX expression in a number of extrarenal organs.nnnCONCLUSIONnCAIX is strongly expressed by ccRCC. Although CAIX is associated with outcome in patients with ccRCC, it is not an independent prognostic marker. Furthermore, CAIX expression is apparent in extrarenal organs. As such, exploitation of CAIX as a prognostic marker and therapeutic target merits additional consideration.

Adult UrologyOncology: Adrenal/Renal/Upper Tract/BladderPositive Surgical Margins at Partial Nephrectomy: Predictors and Oncological Outcomes

PURPOSEnThe prognostic significance and optimal management of positive surgical margins following partial nephrectomy remain ill-defined. We combine data from 2 tertiary care intuitions, and report predictors of positive surgical margins and long-term oncological outcomes for patients with positive surgical margins.nnnMATERIALS AND METHODSnClinical, pathological and followup data on 1,344 patients undergoing 1,390 partial nephrectomies for kidney cancer were analyzed. Patients with positive surgical margins on final pathology were treated expectantly. Univariate and multivariable logistic regression models were fit to determine clinicopathological features associated with positive surgical margins. The Kaplan-Meier method was used to estimate freedom from local disease recurrence and metastatic progression. Cox proportional hazards models were used to assess whether positive surgical margin predicted local recurrence or metastatic disease adjusting for tumor size, pathological stage, histological subtype and presence of a solitary kidney.nnnRESULTSnPositive surgical margins were documented in 77 cases (5.5%). Decreasing tumor size and presence of a solitary kidney carried a significantly higher risk of positive surgical margins. The overall 10-year probability of freedom from local disease recurrence was 93% (95% CI 89, 95) and from metastatic progression 93% (95% CI 90, 95), with no significant difference between patients with positive vs negative margins (p = 0.97 and 0.18, respectively). Positive surgical margins were not associated with an increased risk of local recurrence or metastatic disease.nnnCONCLUSIONSnPositive surgical margins in partial nephrectomy specimens do not uniformly portend an adverse prognosis. While every effort should be taken to ensure clear margins, our data suggest that select patients with a positive surgical margin can be safely offered vigilant monitoring without compromising long-term disease-free survival.

Implications of B7-H1 Expression in Clear Cell Carcinoma of the Kidney for Prognostication and Therapy

B7-H1 encompasses a recently discovered cell surface glycoprotein within the B7 family of T-cell coregulatory molecules. B7-H1 expression can be induced on activated T lymphocytes and is normally expressed by macrophage lineage cells. In addition, some human tumors acquire the ability to aberrantly express B7-H1. Tumor-associated B7-H1, as well as B7-H1 on activated lymphocytes, has been shown to impair antigen-specific T-cell function and survival in vitro. In contrast, in vivo monoclonal antibody–mediated blockade of B7-H1 has been shown to potentiate antitumoral responses in several murine cancer models. Consequently, tumor-associated B7-H1 has garnered much attention in the recent literature as a potential inhibitor of host antitumoral immunity. Our group has recently reported that B7-H1 is aberrantly expressed in both primary and metastatic renal cell carcinoma (RCC) as revealed via immunohistochemical staining of both fresh-frozen and paraffin-embedded nephrectomy specimens. In addition, we have shown that B7-H1 expression by clear cell RCC tumors (or infiltrating mononuclear cells) correlates with aggressive pathologic features, including advanced tumor-node-metastasis stage, tumor size, higher nuclear grade, and coagulative necrosis. In one study of 306 patients, with a median clinical follow-up of 11 years, we reported that RCC B7-H1 expression correlates with increased risk of disease progression, cancer-specific death, and overall mortality even after multivariate adjustment. Five-year cancer-specific survival rates in this study were 42% and 83% for patients harboring B7-H1+ versus B7-H1− RCC tumors, respectively. Such associations may relate to the recognized ability of B7-H1 to inhibit T-cell–mediated antitumoral immunity. In summary, B7-H1 encompasses a potent independent predictor of prognosis for patients with RCC and an extremely promising target to facilitate immunotherapeutic responses during the management of this treatment-refractory tumor.

TLR3-stimulated dendritic cells up-regulate B7-H1 expression and influence the magnitude of CD8 T cell responses to tumor vaccination.

Agonists of TLR have been explored as vaccine adjuvants for tumor immunotherapy. However, their immunological consequences are not fully understood. Although TLR signaling increases the functional potential of dendritic cells (DCs) for priming T cells, coinduction of potentially negative immunoregulatory capacities may impair effector T cell generation. We examined the expression and function of B7 family costimulatory molecules on DCs after activation with the TLR3 agonist, polyinosinic:polycytidylic acid. We demonstrated that polyinosinic:polycytidylic acid consistently up-regulated both B7-2 and B7-H1 molecules on resident, migratory DCs from spleen and lymph nodes. Depletion or blockade of B7-H1 on activated DCs increased the magnitude of effector CD8 T cell expansion. DC-based or protein-based tumor vaccines, in combination with B7-H1 blockade, induced strong effector CD8 T cell responses, resulting in protective immunity against newly established tumors. Our studies suggest that TLR3 signaling has the potential to up-regulate both positive and negative coregulatory molecules on APCs. Selective blockade of negative regulatory molecules in combination with TLR3 agonist may be an effective strategy for increasing the efficacy of tumor vaccines.

Questionable Relevance of γδ T Lymphocytes in Renal Cell Carcinoma

Adoptive γδ T cell immunotherapy has moved briskly into clinical trials prompted by several small studies suggesting abundant accumulation of γδ T cells within renal cell carcinoma (RCC). In this study, we re-examined levels of γδ T cells within RCC tumors and correlated levels of these cells with pathologic features and outcome associated with this form of cancer. Tissues from 248 consecutive clear cell RCC tumors obtained from 2000 to 2003 were stained and quantified for total CD3+ and γδ T cells per mm2. Wilcoxon rank sum and Kruskal-Wallis tests were used to evaluate associations between T cell amounts and prognostic factors (age, gender, tumor size, stage, grade, tumor necrosis). Cox models were used to assess associations with RCC-specific death. Median numbers of total CD3+ and γδ T cells were 281/mm2 (interquartile range (IQR): 149–536) and 2.6/mm2 (IQR: 1.3–4.6), respectively. The median percentage of CD3+ T cells that were γδ T cells was 1.0% (IQR: 0.4–1.9). This low percentage of intratumoral γδ T cells was diluted even further with rising CD3+ T cell infiltration. Percentages of γδ T cells were not associated with even one single clinicopathologic feature examined. Median follow-up for this study was 3.1 years (48 patients died of RCC) and Cox analysis failed to demonstrate that γδ T cells (hazard ratio = 1.02, p = 0.25) were predictive of RCC-specific death. γδ T cells are rare and not recruited nor expanded within RCC tumors. Percentages of γδ T cells fail to correlate with any prognostic features of RCC nor specific death. As such, the role of γδ T cells in RCC immunobiology remains questionable.

Early effects of pharmacological androgen deprivation in human prostate cancer

To assess the early histological effects of pharmacological androgen deprivation (AD), which have been assessed only over longer periods, as surgical castration leads rapidly to diminished cell proliferation and enhanced cell death within the prostate.

NOVEL THERAPEU TIC APPROACHES TO ADVANCED PROSTATE CANCER

For over half a century, the treatment of patients with advanced stages of prostate cancer has been limited to medical or surgical castration. Although this approach has resulted in disease stabilization and regression in some patients, there is a clear need for novel and innovative strategies against this disease. Prostate cancer remains one of the most common causes of cancer death in American men. Though screening has changed the stage of initial presentation for many patients, little progress has been made in those presenting with advanced disease over the last few decades. More recently, an improved understanding of the basic biologic steps in prostate cancer inception and progression has identified a number of disease mechanisms. These mechanisms represent intriguing novel pharmacologic targets for patients that either present with or