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.

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.

• Authors: Silvia Darb-Esfahani, Catarina Alisa Kunze, Hagen Kulbe, Jalid Sehouli, Stephan Wienert, Judith Lindner, Jan Budczies, Michael Bockmayr, Manfred Dietel, Carsten Denkert, Ioana Braicu, Korinna Jöhrens
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 2 Pg. 1486-99 (Jan 12 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26625204 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• RNA, Messenger

Topics

• B7-H1 Antigen (analysis, genetics)
• Biomarkers, Tumor (analysis, genetics)
• Carcinoma (chemistry, genetics, immunology, therapy)
• Databases, Genetic
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Lymphocytes, Tumor-Infiltrating (chemistry, immunology, pathology)
• Middle Aged
• Neoplasm Grading
• Neoplasms, Cystic, Mucinous, and Serous (chemistry, genetics, immunology, therapy)
• Ovarian Neoplasms (chemistry, genetics, immunology, therapy)
• Programmed Cell Death 1 Receptor (analysis, genetics)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Tissue Array Analysis