title: Tissue-based immune monitoring II: multiple tumor sites reveal immunologic homogeneity in serous ovarian carcinoma.
abstract: The presence of tumor-infiltrating lymphocytes (TILs) in epithelial ovarian cancer indicates a host antitumor response and is associated with improved survival. We wished to determine the extent to which TIL density differs from site to site within a given patient. We initially studied multiple paired metastases from serous ovarian carcinoma obtained at the time of primary debulking. The expression of genes in specific immune-related pathways was profiled on a pilot set of five patients. We then used immunohistochemistry and quantitative PCR to estimate the density of CD3+, CD8+, and FoxP3+ TILs in these same tumors. To extend the findings to a larger cohort, we semiquantitatively measured intraepithelial and stromal TILs in a tissue microarray (TMA) containing both primary tumors and metastases from 50 patients. In the pilot group, genes related to antimicrobial signaling and TGF-beta signaling showed between-site heterogeneity, whereas cytokines and antigen presentation transcripts were more homogeneous in any given patient. IHC and qPCR for T cell markers were concordant. In the TMA cohort, 2-way ANOVA showed that TIL heterogeneity between sites was present in some but not all patients. The stroma of extra-ovarian metastases showed significantly greater TIL infiltration than ovarian sites. A simulation showed that at clinically meaningful levels of precision, up to 3% of patients will be misclassified for intraepithelial TILs by a single biopsy. In conclusion, between-site heterogeneity exists in some patients with metastatic serous ovarian cancer. The predictive value of biopsies should be considered in clinical trial design.
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecologic Oncology, University of Pennsylvania, Philadelphia, USA.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Hagemann
authors.forename: Ian S
authors.initials: IS
authors.lastname: Hagemann
authors.forename: Mark
authors.initials: M
authors.lastname: Cadungog
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hwang
authors.forename: Priya
authors.initials: P
authors.lastname: Patel
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.forename: Rachel
authors.initials: R
authors.lastname: Hammond
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Christina S
authors.initials: CS
authors.lastname: Chu
authors.forename: Steven C
authors.initials: SC
authors.lastname: Rubin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D000368:Aged; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D016000:Cluster Analysis; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D015166:Monitoring, Immunologic / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis / Q000379:methods*
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors