Division of Gynecologic Oncology/Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA.
Gynecol Oncol. 2010 Mar;116(3):556-62. doi: 10.1016/j.ygyno.2009.11.020. Epub 2009 Dec 14.
The objective of this study was to examine the clinicopathologic correlates of T-regulatory (T(reg)) cell infiltration in serous ovarian cancers and to define gene signatures associated with high T(reg)s.
Tumor infiltrating T(reg) and cytotoxic T-cells (CTLs) were quantitated in 232 primary serous ovarian cancers by immunostaining for FOXP3 and CD8. Expression microarray analysis was performed in a subset of 48 advanced cancers with the highest and lowest numbers of infiltrating T(reg)s and a genomic signature was developed using binary regression. ANOVA analysis was performed to assess the most differentially expressed genes and these genes were further assessed using Ingenuity Pathway Analysis (IPA) software.
High T(reg) infiltration in ovarian cancers was associated with high grade (p<0.0001), advanced stage (p=0.004) and suboptimal debulking (p<0.04), but not with survival. In contrast, high tumor infiltrating CD8 CTL infiltration was associated with favorable survival (median survival 48.7 vs. 34.6 months, p=0.01). A microarray-based genomic signature for high tumor-infiltrating T(reg) cells had a 77% predictive accuracy using leave-one-out cross-validation. ANOVA of microarray data revealed the antigen presentation pathway as the most differentially expressed canonical pathway (p<0.00001) between cancers with high and low T(reg) cells.
These data suggest that there may be an association between increased T(reg) cell infiltration in ovarian cancers and advanced stage. Increased T(reg) infiltration is characterized by a genomic signature enriched with several immunologic pathway genes. Therapeutic strategies that reduce tumor infiltrating T(reg) cells are under investigation and may prove useful in ovarian cancers with high numbers of these cells.
本研究旨在探讨调节性 T 细胞（Treg）浸润在浆液性卵巢癌中的临床病理相关性，并确定与高 Treg 相关的基因特征。
通过免疫组化法检测 FOXP3 和 CD8，对 232 例原发性浆液性卵巢癌中的肿瘤浸润性 Treg 和细胞毒性 T 细胞（CTL）进行定量分析。对 48 例晚期癌症中浸润性 Treg 数量最高和最低的亚组进行表达微阵列分析，并使用二项回归开发基因组特征。采用方差分析（ANOVA）评估差异表达最显著的基因，并使用 IPA 软件对这些基因进行进一步评估。
卵巢癌中高 Treg 浸润与高级别（p<0.0001）、晚期（p=0.004）和减瘤术不彻底（p<0.04）有关，但与生存无关。相比之下，高肿瘤浸润 CD8 CTL 浸润与良好的生存相关（中位生存 48.7 与 34.6 个月，p=0.01）。基于微阵列的高肿瘤浸润 Treg 细胞基因组特征的留一法交叉验证准确率为 77%。微阵列数据分析的 ANOVA 显示，抗原呈递途径是高 Treg 和低 Treg 细胞之间差异最显著的经典途径（p<0.00001）。
这些数据表明，卵巢癌中 Treg 细胞浸润增加可能与晚期有关。增加的 Treg 浸润表现为富含多种免疫途径基因的基因组特征。正在研究减少肿瘤浸润性 Treg 细胞的治疗策略，这些策略可能对这些细胞数量较多的卵巢癌有用。
