Temporal and spatial heterogeneity of programmed cell death 1-Ligand 1 expression in malignant mesothelioma

Background: Programmed Cell Death 1-Ligand 1 (PD-L1) and Programmed Death Protein 1 (PD-1) blocking antibodies are promising immunotherapies for malignancies. We have previously shown PD-L1 expression in 40% of malignant mesothelioma (MM); however, the temporal and spatial heterogeneity of its expression has not been thoroughly studied. We compared PD-L1 expression between paired primary and metastatic MM. Design: Pathology files (1995-2016) were searched for MM with tissue from multiple sites and/or time points. PD-L1 (clone SP263) expression was reviewed by 2 authors. Mesothelioma cell lines (H2461, One 58, EM-MESO) were cultured with or without vinorelbine or pemetrexed. Following incubation, PD-L1 expression (clone MIH1) was analyzed by flow cytometry. Results: 64 patients (53 men, median age, 64 years) with epithelioid (N = 50), biphasic (N = 11) or sarcomatoid (N = 2) MM or well differentiated papillary mesothelioma (N = 1) (pleural, n = 56; peritoneal, n = 8) were included. Patients had a subsequent specimen from the primary site (n = 48), from a metastasis (n = 6), or both (n = 10). Reviewers agreed on PD-L1 expression in 133 of 151 (88%) specimens. There was agreement of PD-L1 expression between paired primary lesions obtained at separate time points in 47 of 58 (81%) and between paired primary and metastatic lesions in 11 of 16 (69%) cases. A significant increase in PD-L1 expression was observed in all 3 MM cell lines (p < 0.003 each) following exposure to vinorelbine but not to pemetrexed. Conclusion: Overall there is good agreement in PD-L1 expression between paired MM lesions; however, the 19-31% of cases with discordant PD-L1 expression, and the dynamics of PD-L1 expression may limit its use as a predictive biomarker for therapy.