High intratumoral CD8+ T-cell infiltration is associated with improved survival in prostate cancer patients undergoing radical prostatectomy.

BACKGROUND: A high density of CD8+ tumor infiltrating lymphocytes (TILs) is associated with improved survival in multiple cancers, but its prognostic role in prostate cancer remains controversial. The aim of our study was to evaluate the prognostic value of CD8+ TILs in prostate cancer patients undergoing radical prostatectomy (RP). We hypothesized that elevated density of CD8+ TILs in the RP specimen would correlate with improved clinical outcomes. This information may be helpful for future immunotherapy clinical trial design and treatment selection. METHODS: Tumor microarrays constructed from 230 patients with localized prostate cancers who underwent RP from 2006 to 2012 at Roswell Park Comprehensive Cancer Center were analyzed retrospectively using immunohistochemistry. CD8+ cell density was evaluated using a computerized scoring system. The cohorts were separated by CD8+ TIL density at the 25th percentile (i.e., low 7 or pT3/4). The median follow-up time was 8.4 years. High CD8+ TIL density was associated with improved 5-year overall survival (98% vs. 91%, p = .01) and prostate cancer-specific survival (99% vs. 95%, p = .04) compared with patients with low CD8+ TIL density. There was a trend toward higher 5-year biochemical recurrence-free survival and metastasis-free survival in the cohort of patients with high CD8+ TIL density (52% vs. 38% and 86% vs. 73%, respectively), although the difference did not reach statistical significance (p = .18 and p = .05, respectively). In a multivariate analysis high CD8+ TIL density was an independent favorable prognostic factor for overall survival (hazards ratio = 0.38; 95% confidence interval: 0.17-0.87; p = .02). In contrast to the prognostic value of CD8+ TIL density, the CD8+ cell density in the matched normal prostate tissue was not associated with any clinical outcomes. CONCLUSION: Intratumoral CD8+ T-cell infiltration in the RP specimen is independently associated with improved survival after RP in this high-risk prostate cancer cohort. Pre-RP immunomodulation that promotes intratumoral CD8+ cytotoxic T-cell infiltration may be beneficial for this population.

TP53 Status as a Determinant of Pro- vs Anti-Tumorigenic Effects of Estrogen Receptor-Beta in Breast Cancer.

BACKGROUND: Anti-tumorigenic vs pro-tumorigenic roles of estrogen receptor-beta (ESR2) in breast cancer remain unsettled. We investigated the potential of TP53 status to be a determinant of the bi-faceted role of ESR2 and associated therapeutic implications for triple negative breast cancer (TNBC). METHODS: ESR2-TP53 interaction was analyzed with multiple assays including the in situ proximity ligation assay. Transcriptional effects on TP53-target genes and cell proliferation in response to knocking down or overexpressing ESR2 were determined. Patient survival according to ESR2 expression levels and TP53 mutation status was analyzed in the basal-like TNBC subgroup in the Molecular Taxonomy of Breast Cancer International Consortium (n = 308) and Roswell Park Comprehensive Cancer Center (n = 46) patient cohorts by univariate Cox regression and log-rank test. All statistical tests are two-sided. RESULTS: ESR2 interaction with wild-type and mutant TP53 caused pro-proliferative and anti-proliferative effects, respectively. Depleting ESR2 in cells expressing wild-type TP53 resulted in increased expression of TP53-target genes CDKN1A (control group mean [SD] = 1 [0.13] vs ESR2 depletion group mean [SD] = 2.08 [0.24], P = .003) and BBC3 (control group mean [SD] = 1 [0.06] vs ESR2 depleted group mean [SD] = 1.92 [0.25], P = .003); however, expression of CDKN1A (control group mean [SD] = 1 [0.21] vs ESR2 depleted group mean [SD] = 0.56 [0.12], P = .02) and BBC3 (control group mean [SD] = 1 [0.03] vs ESR2 depleted group mean [SD] = 0.55 [0.09], P = .008) was decreased in cells expressing mutant TP53. Overexpressing ESR2 had opposite effects. Tamoxifen increased ESR2-mutant TP53 interaction, leading to reactivation of TP73 and apoptosis. High levels of ESR2 expression in mutant TP53-expressing basal-like tumors is associated with better prognosis (Molecular Taxonomy of Breast Cancer International Consortium cohort: log-rank P = .001; hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.84, univariate Cox P = .02). CONCLUSIONS: TP53 status is a determinant of the functional duality of ESR2. Our study suggests that ESR2-mutant TP53 combination prognosticates survival in TNBC revealing a novel strategy to stratify TNBC for therapeutic intervention potentially by repurposing tamoxifen.