Ricerc@Sapienza

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have an established impact on the prognosis of high-grade
serous ovarian carcinoma (HGSOC), however, their role in recurrent ovarian cancer is largely unknown. We
therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2) expression in the progression
of HGSOC. EXPERIMENTAL DESIGN: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by
immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by
image analysis. All patients had been included to the EU-funded OCTIPS FP7 project. RESULTS: CD3+, CD4+,
CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent
tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; Pb.0001 each). Paired testing revealed higher CD4+ densities and MHC1 expression in recurrent tumors (Wilcoxon P=.034 and P=.018). There was also
a shift towards higher CD3+ TILs levels in recurrent carcinomas when analyzing platinum-sensitive tumors only
(Wilcoxon P=.026) and in pairs with recurrent tumor tissue from first relapse only (Wilcoxon P=.031). High MHC2
expression was the only parameter to be significantly linked to prolonged progression-free survival after first
relapse (PFS2, log-rank P=.012). CONCLUSIONS: This is the first study that analyzed the development of TILs
density and MHC expression in paired primary and recurrent HGSOC. The level of the antitumoral immune
response in recurrent tumors was clearly dependent on the one in the primary tumor. Our data contribute to the
understanding of temporal heterogeneity of HGSOC immune microenvironment and have implications for
selection of samples for biomarker testing in the setting of immune-targeting therapeutics.