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
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Silvia Darb-Esfahani1,2,*, Catarina Alisa Kunze1,*, Hagen Kulbe2,3, Jalid Sehouli2,3, Stephan Wienert1,4, Judith Lindner1, Jan Budczies1, Michael Bockmayr1, Manfred Dietel1, Carsten Denkert1,2, Ioana Braicu2,3 and Korinna Jöhrens1
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
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
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.
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