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

Our plain-English summary of 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, by S. Khanna, A. Thomas, D. Abate-Daga, et al (Journal of Thoracic Oncology, 2016).

The study

• Authors: S. Khanna, A. Thomas, D. Abate-Daga, J. Zhang, B. Morrow, S.M. Steinberg, A. Orlandi, P. Ferroni, J. Schlom, F. Guadagni, R. Hassan
• Journal: Journal of Thoracic Oncology
• Published: 2016;11(11):1993-2005
• Cited by: 89 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

Published by Elsevier Inc.

In plain English

This U.S. National Cancer Institute (NCI) laboratory study examined PD-L1, a protein that can help tumors avoid immune attack, in mesothelioma. It did not study asbestos exposure. The authors stained tumors from 65 patients with pleural or peritoneal mesothelioma seen at the NCI between 1993 and 2012. Of these, 41 (63%) were PD-L1 positive, with similar rates in pleural (62%) and peritoneal (64%) samples. Median overall survival was 23.0 months for patients with PD-L1 positive tumors and 33.3 months for PD-L1 negative tumors. This difference was not statistically significant (p=0.35). In seven patients, T cells in fluid around the tumor (effusions) carried PD-L1 more often than T cells in their blood (p=0.016). In laboratory cultures of one patient's ascites cells, immune cells reacted to that patient's tumor cells. Tumor cells grown for three weeks with these immune cells and IL-2 showed more PD-L1. In laboratory tests, the antibody drug avelumab with natural killer cells killed cells from two of three patient-derived mesothelioma cell lines. The authors concluded that mesothelioma is characterized by high PD-L1 expression. They wrote that this could make it susceptible to drugs targeting PD-L1 or PD-1.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of patient samples: PD-L1 immunohistochemistry on archival tumors with survival analysis, flow cytometry of malignant effusions and blood, and in-vitro co-culture and antibody-dependent cellular cytotoxicity (ADCC) experiments
• Who was studied: Tumor staining: 65 patients with malignant pleural (21) or peritoneal (44) mesothelioma evaluated at the NCI between 1993 and 2012. Other samples: 9 malignant effusions (6 ascites, 3 pleural fluid), paired effusion and blood samples from 7 patients, and 3 primary mesothelioma cell lines.
• Exposure: No asbestos or fiber exposure was studied. The experimental agent was the anti-PD-L1 antibody avelumab, tested in the laboratory with natural killer cells against mesothelioma cell lines.
• Main results:
  • 41 of 65 mesothelioma tumors (63%) were PD-L1 positive (at least 5% of tumor cells staining)
  • PD-L1 positivity was similar in pleural (62%) and peritoneal (64%) mesothelioma samples
  • Males more often had PD-L1 positive tumors than females (73% vs. 46%; p=0.04)
  • Median overall survival was 23.0 months for patients with PD-L1 positive tumors vs. 33.3 months for PD-L1 negative tumors (p=0.35)
  • The hazard ratio for death, PD-L1 positive vs. negative tumors, was 1.30 (95% CI 0.75-2.26). The authors stated the difference was not statistically significant.
  • In 9 malignant effusion samples, the share of cells expressing PD-L1 ranged from about 12% to 83%
  • In 7 patients with paired samples, 7-82% of CD3+ T cells in effusions expressed PD-L1, vs. 0.5-9% in blood
  • PD-L1 expression on CD3+ T cells was significantly higher in effusions than in blood in the 7 paired patients (p=0.016)
  • PD-1 on CD4+ T cells did not differ significantly between effusions and blood (p=0.94)
  • PD-1 on CD8+ T cells was higher in effusions than in blood in 6 of 7 patients, but the difference was not statistically significant (p=0.078)
  • PD-1 expressing CD14+ monocytes were significantly higher in effusions than in blood of the same patients (p=0.031)
  • In laboratory co-cultures of cells from one patient's ascites (NCI-Meso29), lymphocytes released IFN-gamma (mean 1448 pg/mL) in the presence of the patient's own tumor cells
  • In the same cultures, tumor cells grown for 3 weeks with IL-2 and lymphocytes showed marked PD-L1 overexpression compared with tumor cells grown without them
  • Control lung adenocarcinoma cell line H441: the highest avelumab-mediated specific killing was 49.7% at a 25:1 effector-to-target ratio
  • NCI-Meso21 cells (weak PD-L1, tested with healthy-donor natural killer cells): maximum specific killing with avelumab was 13% at the highest effector-to-target ratio
  • With the patient's own natural killer cells, NCI-Meso29 cells showed 23% specific lysis at a 25:1 ratio, while avelumab did not mediate killing of NCI-Meso49 cells
• The authors' conclusion: The authors concluded that malignant mesothelioma is characterized by high PD-L1 expression, and that malignant effusions show PD-L1 on tumor cells and infiltration by PD-L1 and PD-1 positive immune cells. They wrote that effusion lymphocytes could dampen the immune response by inducing PD-L1. They also wrote that these checkpoints could make mesothelioma susceptible to agents targeting PD-L1 or PD-1.
• Limitations the authors state:
  • It is not known whether malignant effusions fully reflect the biology of the tumor microenvironment
  • PD-L1 immunohistochemistry is affected by unresolved issues, including differences in antibodies, tissue processing and positivity cutoffs
  • PD-L1 expression varies over time and with many factors, so any measurement is a snapshot in time

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, PD-L1, Mesothelioma, Immunohistochemistry, Peritoneal Mesothelioma, Overall Survival.

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