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Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer.

ABSTRACT: The immune system constitutes one of the host factors modifying outcomes in ovarian cancer. Regulatory T cells (Tregs) are believed to be a major factor in preventing the immune response from destroying ovarian cancers. Understanding mechanisms that regulate Tregs in the tumor microenvironment could lead to the identification of novel targets aimed at reducing their influence. In this study, we used immunofluorescence-based microscopy to enumerate Tregs, total CD4 T cells, and CD8(+) cytotoxic T cells in fresh frozen tumors from over 400 patients with ovarian cancer (>80 % high-grade serous). We sought to determine whether Tregs were associated with survival and genetic variation in 79 genes known to influence Treg induction, trafficking, or function. We used Cox regression, accounting for known prognostic factors, to estimate hazard ratios (HRs) associated with T cell counts and ratios. We found that the ratios of CD8 T cells and total CD4 T cells to Tregs were associated with improved overall survival (CD8/Treg HR 0.84, p = 0.0089; CD4/Treg HR 0.88, p = 0.046) and with genetic variation in IL-10 (p = 0.0073 and 0.01, respectively). In multivariate analyses, the associations between the ratios and overall survival remained similar (IL-10 and clinical covariate-adjusted CD8/Treg HR 0.85, p = 0.031; CD4/Treg HR 0.87, p = 0.093), suggesting that this association was not driven by variation in IL-10. Thus, integration of novel tumor phenotyping measures with extensive clinical and genetic information suggests that the ratio of T cells to Tregs may be prognostic of outcome in ovarian cancer, regardless of inherited genotype in genes related to Tregs.

SUBMITTER: Knutson KL

PROVIDER: S-EPMC4651184 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer.

Knutson Keith L KL Maurer Matthew J MJ Preston Claudia C CC Moysich Kirsten B KB Goergen Krista K Hawthorne Kieran M KM Cunningham Julie M JM Odunsi Kunle K Hartmann Lynn C LC Kalli Kimberly R KR Oberg Ann L AL Goode Ellen L EL

Cancer immunology, immunotherapy : CII 20150823 12

The immune system constitutes one of the host factors modifying outcomes in ovarian cancer. Regulatory T cells (Tregs) are believed to be a major factor in preventing the immune response from destroying ovarian cancers. Understanding mechanisms that regulate Tregs in the tumor microenvironment could lead to the identification of novel targets aimed at reducing their influence. In this study, we used immunofluorescence-based microscopy to enumerate Tregs, total CD4 T cells, and CD8(+) cytotoxic T ...[more]

PMID: 26298430

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Project description:BackgroundEpithelial ovarian cancer (EOC) is an aggressive disease with poor prognosis. The expression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) correlates with the malignant progression of several cancers. However, the relationship between the subcellular localization of CIAPIN1 and clinical characteristics in EOC remains unclear.MethodsImmunohistochemistry was performed to detect CIAPIN1 expression in 108 EOC tissues. CIAPIN1 expressions in eight fresh EOC tissues were detected by Western blotting. The relationship between CIAPIN1 subcellular expression and patients' clinicopathological features, including prognosis, was evaluated. Immunohistochemistry and immunofluorescence were employed to assess the CIAPIN1 subcellular localization in the EOC cell lines A2780 and HO8910. In addition, all patients were followed up to assess the prognostic value of CIAPIN1 in patients with EOC.ResultsCIAPIN1 is highly expressed in EOC, but is present at low levels in paired non-cancerous ovarian epithelial tissues. The results of Western blotting were in accordance with the immunohistochemical results. Poor differentiation of the tumors and EOC cell lines correlated with higher levels of CIAPIN1 nuclear expression. CIAPIN1 nuclear expression significantly correlated with the Federation International of Gynecology and Obstetrics (FIGO) stage and histological differentiation (P?=?0.034 and P?<?0.0001, respectively). Moreover, nuclear localization of CIAPIN1 was selected as an unfavorable prognostic factor by both univariate and multivariate analyses ( P?<?0.001). However, no significant correlations were observed between cytoplasmic localization of CIAPIN1 and clinicopathological parameters.ConclusionsCIAPIN1 might play a crucial role in the differentiation of EOC cells. Elevated expression of nuclear CIAPIN1 negatively correlated with the survival of EOC patients, suggesting that nuclear CIAPIN1 might serve as a prognostic biomarker for EOC patients.

Project description:There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer.We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival.The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047).This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is only statistically significant for intratumoral TILs. This study suggests that a clinically useful immune prognostic indicator in epithelial ovarian cancer could be developed using this technique.

Project description:BACKGROUND:Mitochondria are the site of oxidative phosphorylation, a process which generates reactive oxygen species (ROS). Elevated ROS levels can lead to oxidative stress, a cellular state implicated in carcinogenesis. It is hypothesized that alternations in mitochondrial (MT) DNA, including heritable MT single nucleotide polymorphisms (MT-SNPs), have the potential to change the capacity of MT function, leading to increased oxidative stress and cancer risk. We investigated if common MT-SNPs and/or haplogroups and are associated with invasive serous ovarian cancer (OvCa) risk. METHODS:A panel of 64 MT-SNPs designed to tag all common variation in the European MT genome (minor allele frequency (MAF) >1%, r^2 >0.8) was genotyped in study participants of European descent using the Sequenom MassARRAY iPlex Gold® system (Sequenom Inc, CA, USA). Invasive serous OvCa cases (n?=?405) and frequency age-matched controls (n?=?445) were drawn from a population-based case-control study of OvCa in western Canada. Binary logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (C.I.) for carriage of the minor versus major allele by case-control status. MitoTool was used to test the relationship between European haplogroup status and case-control status using Fisher's exact test. RESULTS:The most significant disease-SNP association was for rs2857285, a synonymous MT-SNP in ND4 (OR?=?4.84, 95% CI: 1.03-22.68, P?=?0.045). After adjustment for multiple testing using a Bonferroni correction of the Type 1 error this MT-SNP was not significant. No other MT-SNP had a P-value?<?0.05. European haplogroup status was not associated with case status. Most MT-SNPs (73%) genotyped had a MAF <5%. CONCLUSION:Common European MT-SNPs (MAF?>?5%) and haplogroups were not associated with invasive serous OvCa risk in this study; however, most European MT-SNPs have a low MAF (<5%), which we were underpowered to adequately assess. Larger studies are needed to clarify the role of low MAF MT-SNPs (MAF?<?5%) in invasive serous OvCa risk.

Project description:BACKGROUND:ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. METHODS:The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. RESULTS:Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. CONCLUSIONS:Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.

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Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer.

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Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer.

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