Evaluation of PD-L1 expression in a large set of gastroenteropancreatic neuroendocrine tumours and correlation with clinicopathological data.

Background: Targeting programmed death protein 1 (PD-1) or its ligand PD-L1 is a promising therapeutic approach for many types of cancer in which PD-L1 is overexpressed. However, data on PD-L1 expression levels in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are limited and contradictory.

Methods: We evaluated PD-L1 expression in 457 archived, formalin-fixed, paraffin-embedded GEP-NEN samples from 175 patients by immunohistochemistry using the highly sensitive monoclonal anti-PD-L1 antibody 73-10. The immunostaining was semiquantitatively evaluated using a 12-point immunoreactivity score (IRS) taking both PD-L1-positive tumour cells and immune cells into account. Tumour samples with an IRS ≥ 3 were considered PD-L1-positive. Results were correlated with clinicopathological data and with the expression of several typical markers and receptors for neuroendocrine tumours.

Results: Of the GEP-NEN samples, 73% were PD-L1-positive. The median IRS value across all samples was 4.0, corresponding to low expression. PD-L1 immunostaining was predominantly localised at the plasma membrane of the tumour cells. Positive correlations were observed between PD-L1 expression and tumour grading or Ki-67 index, between PD-L1 expression and the expression of chromogranin A, and between PD-L1 expression and the expression of each of the five somatostatin receptors. PD-L1 expression was lower in tumours with lymph node metastases at diagnosis than in those without regional metastasis and lower in high-stage than in earlier-stage tumours. No association was noted between PD-L1 expression and patient survival.

Conclusions: PD-L1 expression is common in GEP-NENs and increases with malignancy. Therefore, especially in high-grade GEP-NENs, targeting the PD-1/PD-L1 axis could be a promising additional therapeutic strategy.