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S. Khanna

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    ORAL 40 - Biology 1 (ID 154)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      ORAL40.01 - PD-L1 Is Highly Expressed in Malignant Mesothelioma and PD-1<sup>+ </sup>Lymphocytes within Malignant Effusions Induce PD-L1 Expression (ID 553)

      16:45 - 18:15  |  Author(s): S. Khanna

      • Abstract
      • Presentation
      • Slides

      The PD-1 and PD-L1 pathway is an immune checkpoint, which protects normal tissues from immune attack by curbing the effector T-cell response but can also prevent anti-tumor immune response. However their role in mesothelioma is not well understood. The present study aimed to understand the PD-1 and PD-L1 expression levels and their interactions in mesothelioma patients.

      Sections of formalin-fixed, paraffin-embedded pleural and peritoneal mesothelioma tumor samples from patients who were evaluated for various clinical trials at the NCI Center for Cancer Research were tested for PD-L1 expression (Anti-PD-L1 rabbit monoclonal recombinant primary antibody MKP-1B-196-10; Merck-Serono). PD-L1 expression on primary and established mesothelioma cell lines, malignant pleural effusions and ascites of mesothelioma patients were assessed using a commercial anti-PD-L1 antibody and analyzed by flow cytometry. Paired malignant effusion and peripheral blood samples were tested for PD-1 and PD-L1 expression on immune cells. Co-cultures of autologous tumor cells and T cells grown from malignant effusions of a mesothelioma patient were evaluated to understand the PD-1 and PD-L1 interaction.

      Tumor samples from 65 patients included 44 peritoneal and 21 pleural mesotheliomas; 55 with epithelioid histology and 10 of other subtypes (sarcomatoid 2, biphasic 3, uncategorized 5). 41 of 65 (63%) tumors were positive for PD-L1 expression (defined as >5% PD-L1 expression on tumor cells, of any intensity) with levels of expression ranging from 5% to 80% of tumor cells, and intensities from 1+ to 3+. 24 (37%) were negative including 10 with focal staining. A higher proportion of males had tumor PD-L1 expression than females (73% vs. 46%; p=0.04). There was no association between PD-L1 expression and primary site of disease, age, race, histology and distant metastasis. Patients with PD-L1 positive tumors had a numerically inferior overall survival than patients with PD-L1 negative tumors (23.0 months vs.33.3 months; p=0.35). All 6 primary and 4 established mesothelioma cell lines tested showed basal expression of PD-L1. This was enhanced on treatment with IFN-γ. The fraction of cells expressing PD-L1 in malignant effusions ranged from 17 to 43%. Malignant effusions from 2 of 3 patients had high PD-1 expression on both CD4[+] and CD8[+] T cells. In addition, CD8[+] T cells in malignant effusions had significantly higher levels of PD-L1 expression compared to CD8[+] T cells in peripheral blood (7.47±2.75 % T cells versus 1.97±1.22% T cells; p=0.03). Autologous lymphocytes when co-cultured with tumor cells from malignant effusion, recognized tumor cells and induced IFN-γ mediated PD-L1 expression on their surface.

      High PD-L1 expression in mesothelioma patient tumor samples and tumor cells derived from malignant effusions, as well as presence of PD-1[+] T cells in these effusions indicates the prominent role of PD-1/PD-L1 pathway in maintaining an immunosuppressive milieu in mesothelioma. Thus, inhibiting this pathway could be useful therapeutically.

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