Between-Site Variability in Immune Response to Metastatic Serous Ovarian Carcinoma
IS Hagemann, AR Hagemann, P Lal, G Coukos, MD Feldman. University of Pennsylvania, Philadelphia, PA
Background: The presence of tumor-infiltrating lymphocytes (TILs) in epithelial ovarian carcinoma predicts significantly improved survival. Immunomodulation might thus offer important therapeutic opportunities in ovarian cancer. It is not well established, however, whether the presence, distribution, or activity of these TILs is different in metastatic tumor deposits as compared to the primary lesion. Between-site heterogeneity could explain the resistance of certain tumor sites to immunotherapy and provide guidance for treating residual disease.
Design: We retrieved a series of 53 cases of metastatic serous ovarian cancer (stages IIIC and IV) resected at our institution between 2005 and 2008. H&E-stained slides were reviewed and blocks were selected to construct a tissue microarray of primary and metastatic tumors. Immunostains for immune markers CD3 (pan T lymphocyte), CD8 (cytotoxic T lymphocyte), and FoxP3 (T regulatory lymphocyte) were performed. Staining in three cores from a primary tumor and two metastases (nine cores/case) was semi-quantitatively scored using a grading rubric.
Results: TIL counts were higher at metastatic sites than at primary sites (mean score 1.61 versus 1.42; p=0.015 by Mann-Whitney test). For tumor infiltration by CD3+ lymphocytes, there was significant variation between cases (accounting for 47% of the total variance in TIL counts; p<0.0001 by 2-way ANOVA), while the interaction between case and site accounted for a further 30% of the total variance (p<0.0001). Similar results were obtained for FoxP3 and for CD8. The degree of between-site heterogeneity, as assessed for each case by taking the SEM of the TIL scores at each site, was normally distributed by D'Agostino-Pearson test.
Conclusions: The density of TILs in all three populations (CD3+, CD8+, FoxP3+) differed significantly from case to case and from site to site within a given case. Some cases demonstrated greater between-site heterogeneity in the density of TILs. In terms of their propensity to exhibit between-site variation, the cases showed a continuum of behavior rather than a bimodal distribution. We conclude that assessments of tumor immune response derived from a single tumor sample may be inaccurate; further, tumors with greater between-site heterogeneity may be expected to display unique biology, potentially including resistance to immunomodulatory therapy.
Category: Gynecologic & Obstetrics
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 153, Wednesday Afternoon