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

AimsAntibodies 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.MethodsPD-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.ResultsPD-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).ConclusionsDespite 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.

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

“…It is in line with a recent report, showing that PD-1 þ T infiltrating lymphocytes and PD-L1 þ tumor cells were both favorable prognostic factors in ovarian cancer (41). The inverse function of the immune checkpoint molecules in controlling the T-cell activation in other types of cancers was also suggested by several other independent studies (42)(43)(44).…”

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

“…demonstrated PD-1 to be an independent prognostic factor for both OS and disease-free survival in patients with MSS tumours. 17 Moreover, PD-1 expression has been demonstrated to carry an independent favourable impact in gastric, 47 ovarian, 48 and head and neck cancer, 49 among others. Further studies are warranted to elucidate the prognostic impact of PD-1 expression in CRC, particularly regarding PTL.…”

Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging

“…Challenges exist including appropriate trial design, patient selection, dose determination, and complex pharmacokinetics (11). Several potential biomarkers have emerged including programmed death-ligand 1 (PD-L1) or PD-1 expression (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Although PD-L1 expression has been linked to poor prognoses and better therapeutic responses, its true predictive value is still unknown.…”