Intraepithelial T cells and prognosis in ovarian carcinoma: Novel associations with stage, tumor type, and BRCA1 loss

Blaise Clarke, Anna V. Tinker, Cheng Han Lee, Subbaya Subramanian, Matt Van De Rijn, Dmitry Turbin, Steve Kalloger, Guangming Han, Kathy Ceballos, Mark G. Cadungog, David G. Huntsman, George Coukos, C. Blake Gilks

Research output: Contribution to journalArticlepeer-review

177 Scopus citations

Abstract

Intraepithelial tumor-infiltrating T cells have been correlated with improved outcomes in ovarian carcinoma, however, it is not known whether there is an association with disease stage, histological subtype, or BRCA mutation/expression. Two case series of ovarian carcinomas were included in the study; a retrospective series of 500 patients, and 40 prospectively collected cases fully characterized for BRCA1 mutation status and expression. Intraepithelial immune cells were assessed as present or absent by immunohistochemical staining of tissue microarrays. In the retrospective case series, the presence of intraepithelial CD8+ T-cells correlated with improved disease-specific survival (P=0.027), whereas intraepithelial CD3 + T cells did not (P=0.49). For serous ovarian carcinomas, the presence of intraepithelial CD3+ and CD8+ T-cells correlated with improved disease-specific survival (P=0.0016 and P≤0.0001, respectively). The presence of intraepithelial CD8+ T cells was not associated with improved survival in endometrioid or clear cell carcinomas. On multivariate analysis, disease stage and CD8+ T cells were found to be independently predictive of improved disease-specific survival, whereas grade, age at surgery, and type of adjuvant treatment were not. In the prospective patient cohort, intraepithelial CD8+ T-cells correlated with the presence of mutation or loss of expression of BRCA1 through promoter methylation (P=0.019). Intraepithelial CD8+ tumor-infiltrating T-cells correlate with improved clinical outcomes for all stages of ovarian cancer; this association is restricted to the serous ovarian cancer subtype, and is an independent prognostic factor on multivariate analysis. The presence of intraepithelial CD8+ T cells also significantly correlates with loss of BRCA1.

Original languageEnglish (US)
Pages (from-to)393-402
Number of pages10
JournalModern Pathology
Volume22
Issue number3
DOIs
StatePublished - 2009

Bibliographical note

Funding Information:
CBG was supported by the National Cancer Institute of Canada (no. 017051) and an unrestricted educational grant from Sanofi-Aventis. GC was supported by NIH P50-CA083638 Ovarian Cancer SPORE. Blaise Clarke was recipient of a fellowship from Eli Lilly. CBG, SK, and DH received support OvCaRe. Patient outcome data and support in data analysis was provided by the Cheryl Brown Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency.

Keywords

  • BRCA
  • Ovarian carcinoma
  • Prognosis
  • Serous carcinoma
  • T cells
  • Tumor-infiltrating lymphocytes

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