INTRODUCTION: The functional aspects of programmed death 1 (PD-1) and PD ligand 
1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied.
METHODS: Tumor samples from 65 patients with mesothelioma were evaluated for 
PD-L1 expression by immunohistochemistry, and its prognostic significance was 
examined. Malignant effusions from patients with pleural and peritoneal 
mesothelioma were evaluated for PD-1-positive and PD-L1-positive infiltrating 
lymphocytes and their role in inducing PD-L1 expression in tumor cells. 
Antibody-dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized 
immunoglobulin G1 anti PD-L1 antibody against primary mesothelioma cell lines, 
was evaluated in presence of autologous and allogeneic natural killer cells.
RESULTS: Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) 
were PD-L1-positive, which was associated with slightly inferior overall 
survival compared to patients with PD-L1-negative tumors (median 23.0 versus 
33.3 months, p = 0.35). The frequency of PD-L1 expression was similar in 
patients with pleural and peritoneal mesothelioma, with 62% and 64% of samples 
testing positive, respectively. In nine mesothelioma effusion samples evaluated, 
the fraction of cells expressing PD-L1 ranged from 12% to 83%. In seven patients 
with paired malignant effusion and peripheral blood mononuclear cell (PBMC) 
samples, PD-L1 expression was significantly higher on CD3-positive T cells 
present in malignant effusions as compared with PBMCs (p = 0.016). In addition, 
the numbers of CD14-positive PD-1-positive cells were increased in malignant 
effusions compared with PBMCs (p = 0.031). The lymphocytes present in malignant 
effusions recognized autologous tumor cells and induced interferon-γ-mediated 
PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma 
cell lines tested, two were susceptible to avelumab-mediated ADCC in the 
presence of autologous natural killer cells.
CONCLUSIONS: Most pleural as well as peritoneal mesotheliomas express PD-L1. 
Malignant effusions in this disease are characterized by the presence of tumor 
cells and CD3-positive T cells that highly express PD-L1. In addition, 
mesothelioma tumor cells are susceptible to ADCC by the anti-PD-L1 antibody 
avelumab.