Programmed death protein 1 (PD-1) and its ligand, PD-L1, have emerged as promising therapeutic targets for many types of cancer that overexpress PD-L1. However, data on PD-L1 expression levels in bronchopulmonary neuroendocrine neoplasms (BP-NEN) are limited and contradictory. In the present study, a total of 298 archived, formalin-fixed, paraffin-embedded BP-NEN samples from 97 patients diagnosed with typical carcinoid (TC), atypical carcinoid (AC), small cell lung cancer (SCLC), or large cell neuroendocrine carcinoma of the lung (LCNEC) were evaluated for PD-L1 expression by immunohistochemistry using the highly sensitive monoclonal anti-PD-L1 antibody 73-10. PD-L1 expression levels were semiquantitatively estimated by tumour grading. Of the 298 BP-NEN samples, 85% were positive for PD-L1 expression. PD-L1 immunostaining predominantly localized to the plasma membrane of both tumour cells and tumour-infiltrating immune cells. SCLC and LCNEC exhibited significantly higher PD-L1 expression levels than TC or AC. PD-L1 expression levels were also higher in patients with lymph node or distant metastases, in patients who smoked, and in patients who died during the follow-up period. Moreover, PD-L1 expression levels correlated positively with tumour grading, Ki-67 index and the expression of the chemokine receptor CXCR4 and negatively with the levels of somatostatin receptor 1 and chromogranin A. High tumour PD-L1 levels were associated with poor patient outcomes. In conclusion, PD-L1 expression is common in BP-NEN, increases with malignancy, and is associated with poor prognosis. Therefore, targeting the PD-1/PD-L1 axis could be a promising strategy for treating BP-NEN. PD-L1 may also represent a useful prognostic biomarker for this tumour entity.
Erik Rösner, Daniel Kaemmerer, Elisa Neubauer, Jörg Sänger, and Amelie Lupp
Stefan Schulz, Anika Mann, Benjamin Novakhov, Hugh D Piggins, and Amelie Lupp
The vasoactive intestinal peptide receptor 2 (VPAC2) is widely distributed throughout the body and is also overexpressed in a variety of human neoplastic tissues. However, little is known about its precise tissue distribution, regulation and function, which is in part be due to the lack of specific monoclonal anti-VPAC2 antibodies. In this study, we extensively characterised the novel rabbit monoclonal anti-VPAC2 antibody (clone SP235) using transfected cells and mouse, rat and human tissues. SP235 was then subjected to a comparative immunohistochemical study on a series of 167 histological specimens from formalin-fixed, paraffin-embedded human tumours and adjacent normal tissues. SP235 detected a broad band migrating at a molecular weight of 50–70 kDa in western blotting analyses of various mouse tissues as well as VPAC2- but not VPAC1-transfected human embryonic kidney 293 cells. SP235 yielded an efficient immunostaining of distinct cell populations in human tissue samples with a predominance of plasma membrane staining, which was completely abolished by preadsorption with its immunising peptide. SP235 immunohistochemistry detected VPAC2 receptors in lymphocytes present in spleen, tonsils, lymph nodes and Peyer's patches, chief cells of gastric mucosa, exocrine and endocrine pancreas, kidney tubules and blood vessels. In addition, VPAC2 was observed in thyroid, gastric and lung carcinomas, pancreatic adenocarcinomas, sarcomas and neuroendocrine tumours. SP235 may prove of great value in the identification of VPAC2 receptors during routine histopathological examination. VPAC2 visualisation with this simple and rapid immunohistochemical method will facilitate identification of candidate tumours for vasoactive intestinal peptide (VIP)-based diagnostics or therapeutic interventions.