title: PD-L1 expression in small cell neuroendocrine carcinomas.
abstract: Small cell lung cancer and extrapulmonary small cell carcinomas are the most aggressive type of neuroendocrine carcinomas. Clinical treatment relies on conventional chemotherapy and radiotherapy; relapses are frequent. The PD-1/PD-L1/PD-L2 pathway is a major target of anti-tumour immunotherapy. Aberrant PD-L1 or PD-L2 expression may cause local immune-suppression. Here we investigated expression of PD-1 and its ligands by immunohistochemistry and RNA-seq in small cell carcinomas. PD-L1 and PD-1 protein expression were analysed in 94 clinical cases of small cell carcinomas (61 pulmonary, 33 extrapulmonary) by immunohistochemistry using two different monoclonal antibodies (5H1, E1L3N). RNA expression was profiled by RNA-seq in 43 clinical cases. None of the small cell carcinomas showed PD-L1 protein expression in tumour cells. PD-L1 and PD-1 expression was noticed in the stroma: Using immunohistochemistry, 18.5% of cases (17/92) showed PD-L1 expression in tumour-infiltrating macrophages and 48% showed PD-1 positive lymphocytes (45/94). RNA-seq showed moderate PD-L1 gene expression in 37.2% (16/43). PD-L1 was correlated with macrophage and T-cell markers. The second PD-1 ligand PD-L2 was expressed in 27.9% (12/43) and showed similar correlations. Thus, the PD-1/PD-L1 pathway seems activated in a fraction of small cell carcinomas. The carcinoma cells were negative in all cases, PD-L1 was expressed in tumour-infiltrating macrophages and was correlated with tumour-infiltrating lymphocytes. Patients with stromal PD-L1/PD-L2 expression may respond to anti-PD-1 treatment. Thus, evaluation of the composition of the tumour microenvironment should be included in clinical trials. Besides conventional immunohistochemistry, RNA-seq seems suitable for detection of PD-L1/PD-L2 expression and might prove to be more sensitive.
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany. Electronic address: anne.schultheis@uk-koeln.de.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Schultheis
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Scheel
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Ozretić
authors.affiliation: Department of Translational Genomics, University of Cologne, Cologne, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: George
authors.affiliation: Department of Translational Genomics, University of Cologne, Cologne, Germany.
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hagemann
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Cologne/Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Cologne/Bonn, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Cologne/Bonn, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism*; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor
keywords: Immunohistochemistry; PD-L1; Small cell lung cancer; Small cell neuroendocrine carcinoma