title: Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss.
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<or=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.
authors.affiliation: Genetic Pathology Evaluation Center of the Prostate Research Center, Department of Pathology, Vancouver General Hospital and British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Blaise
authors.initials: B
authors.lastname: Clarke
authors.forename: Anna V
authors.initials: AV
authors.lastname: Tinker
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Dmitry
authors.initials: D
authors.lastname: Turbin
authors.forename: Steve
authors.initials: S
authors.lastname: Kalloger
authors.forename: Guangming
authors.initials: G
authors.lastname: Han
authors.forename: Kathy
authors.initials: K
authors.lastname: Ceballos
authors.forename: Mark G
authors.initials: MG
authors.lastname: Cadungog
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D019398:Genes, BRCA1; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D017252:CD3 Complex