Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma

// Silvia Darb-Esfahani 1,2,* , Catarina Alisa Kunze 1,* , Hagen Kulbe 2,3 , Jalid Sehouli 2,3 , Stephan Wienert 1,4 , Judith Lindner 1 , Jan Budczies 1 , Michael Bockmayr 1 , Manfred Dietel 1 , Carsten Denkert 1,2 , Ioana Braicu 2,3 and Korinna Jöhrens 1 1 Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany 2 Tumorbank Ovarian Cancer Network, Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany 3 Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany 4 VM Scope GmbH, Berlin, Germany * These authors have contributed equally to the work Correspondence to: Silvia Darb-Esfahani, email: // Keywords : high grade serous carcinoma, ovarian, PD-1, PD-L1, tumor-infiltrating lymphocytes Received : June 12, 2015 Accepted : November 15, 2015 Published : November 29, 2015 Abstract Aims: Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. Methods: PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset. Results: PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS ( p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets ( p = 0.02 and p < 0.0001, respectively). Conclusions: Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity.