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Malignant Mesothelioma Effusions Are Infiltrated by CD3+ T Cells Highly Expressing PD-L1 and the PD-L1+ Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti-PD-L1 Antibody Avelumab. 2016

Swati Khanna, and Anish Thomas, and Daniel Abate-Daga, and Jingli Zhang, and Betsy Morrow, and Seth M Steinberg, and Augusto Orlandi, and Patrizia Ferroni, and Jeffrey Schlom, and Fiorella Guadagni, and Raffit Hassan
Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied. 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. 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. 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.

UI MeSH Term Description Entries
D008175 Lung Neoplasms Tumors or cancer of the LUNG. Cancer of Lung,Lung Cancer,Pulmonary Cancer,Pulmonary Neoplasms,Cancer of the Lung,Neoplasms, Lung,Neoplasms, Pulmonary,Cancer, Lung,Cancer, Pulmonary,Cancers, Lung,Cancers, Pulmonary,Lung Cancers,Lung Neoplasm,Neoplasm, Lung,Neoplasm, Pulmonary,Pulmonary Cancers,Pulmonary Neoplasm
D008297 Male Males
D008654 Mesothelioma A tumor derived from mesothelial tissue (peritoneum, pleura, pericardium). It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. (Dorland, 27th ed) Mesotheliomas
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000086002 Mesothelioma, Malignant A type of mesothelioma with a tendency to metastasize. Most tumors originate from either the PLEURA or PERITONEUM, tumors may also originate in the PERICARDIUM or testicular tissue. It is associated with ASBESTOS exposure. Somatic mutations identified in WT1, BCL10, CDKN2A, NF2, and BAP1 genes are associated with the malignancy. OMIM: 156240. Malignant Mesothelioma,Malignant Pleural Mesothelioma,Mesothelioma, Malignant Pleural,Malignant Mesotheliomas,Malignant Pleural Mesotheliomas,Mesotheliomas, Malignant,Mesotheliomas, Malignant Pleural,Pleural Mesothelioma, Malignant,Pleural Mesotheliomas, Malignant
D000911 Antibodies, Monoclonal Antibodies produced by a single clone of cells. Monoclonal Antibodies,Monoclonal Antibody,Antibody, Monoclonal
D000920 Antibody-Dependent Cell Cytotoxicity The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface IMMUNOGLOBULIN G whose Fc portion is intact. The effector cell is a "killer" cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent. ADCC,Cytotoxicity, Antibody-Dependent Cell,Cell Cytoxicity, Antibody-Dependent,Antibody Dependent Cell Cytotoxicity,Antibody-Dependent Cell Cytotoxicities,Antibody-Dependent Cell Cytoxicities,Antibody-Dependent Cell Cytoxicity,Cell Cytotoxicities, Antibody-Dependent,Cell Cytotoxicity, Antibody-Dependent,Cell Cytoxicities, Antibody-Dependent,Cell Cytoxicity, Antibody Dependent,Cytotoxicities, Antibody-Dependent Cell,Cytotoxicity, Antibody Dependent Cell,Cytoxicities, Antibody-Dependent Cell,Cytoxicity, Antibody-Dependent Cell
D013601 T-Lymphocytes Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T Cell,T Lymphocyte,T-Cells,Thymus-Dependent Lymphocytes,Cell, T,Cells, T,Lymphocyte, T,Lymphocyte, Thymus-Dependent,Lymphocytes, T,Lymphocytes, Thymus-Dependent,T Cells,T Lymphocytes,T-Cell,T-Lymphocyte,Thymus Dependent Lymphocytes,Thymus-Dependent Lymphocyte
D060890 B7-H1 Antigen An inhibitory B7 antigen that contains V-type and C2 type immunoglobulin domains. It has specificity for the T-CELL receptor PROGRAMMED CELL DEATH 1 PROTEIN and provides negative signals that control and inhibit T-cell responses. It is found at higher than normal levels on tumor cells, suggesting its potential role in TUMOR IMMUNE EVASION. Antigens, CD274,PD-L1 Protein,Programmed Cell Death 1 Ligand 1 Protein,Programmed Death Ligand 1,B7-H1 Immune Costimulatory Protein,B7H1 Immune Costimulatory Protein,CD274 Antigen,PD-L1 Costimulatory Protein,Programmed Cell Death 1 Ligand 1,Antigen, B7-H1,Antigen, CD274,B7 H1 Antigen,B7 H1 Immune Costimulatory Protein,CD274 Antigens,Costimulatory Protein, PD-L1,PD L1 Costimulatory Protein,PD L1 Protein

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