Precision immunotherapy; dynamics in the cellular profile of pleural effusions in malignant mesothelioma patients

Our plain-English summary of Precision immunotherapy; dynamics in the cellular profile of pleural effusions in malignant mesothelioma patients, by L.A. Lievense, K. Bezemer, R. Cornelissen, et al (Lung Cancer, 2017).

The study

• Authors: L.A. Lievense, K. Bezemer, R. Cornelissen, M.E. Kaijen-Lambers, J.P. Hegmans, J.G. Aerts
• Journal: Lung Cancer
• Published: 2017;107:36-40
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Clinical studies have proven the potential of immunotherapy in malignancies. To increase efficacy, a prerequisite is that treatment is tailored, so precision immune-oncology is the logical next step. In order to tailor treatment, characterization of the patient's tumor environment is key. Pleural effusion (PE) often accompanies malignant pleural mesothelioma (MPM) and is an important part of the MPM environment. Furthermore, the composition of PE is used as surrogate for the tumor. In this study, we provide an insight in the dynamics of the MPM environment through characterization of PE composition over time and show that the immunological characteristics of PE do not necessarily mirror those of the tumor.

Materials And Methods: From 5 MPM patients, PE and tumor biopsies were acquired at the same time point. From one of these patients multiple PEs were obtained. PEs were acquired performing thoracocenteses and total cell amounts were determined. Immunohistochemistry was performed to quantify immune cell composition (T cells, macrophages) and tumor cells in PE derived cytospins and tumor biopsies.

Results: The PE amount and (immune) cellular composition varied considerably over time between multiple (n=10) thoracocenteses. These dynamics could in part be attributed to the treatment regimen consisting of standard chemotherapy and dendritic cell (DC)-based immunotherapy. In addition, the presence of T cells and macrophages in PE did not necessarily mirror the infiltration of these immune cells within tumor biopsies in 4 out of 5 patients.

Conclusions: In this proof-of-concept study with limited sample size, we demonstrate that the composition of PE is dynamic and influenced by treatment. Furthermore, the immune cell composition of PE does not automatically reflect the properties of tumor tissue. This has major consequences when applying precision immunotherapy based on PE findings in patients. Furthermore, it implies a regulated trafficking of immune regulating cells within the tumor environment.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In plain English

This retrospective proof-of-concept study looked at the fluid that builds up around the lungs (pleural effusion) in patients with epithelioid malignant pleural mesothelioma. It did not study asbestos exposure. In five patients, the authors compared immune cells in effusion fluid and in tumor biopsies taken at the same time, before treatment. In one patient they also followed 10 fluid drainages over one year, during chemotherapy with cisplatin and pemetrexed and dendritic cell-based immunotherapy. In that patient, the drained fluid ranged from 400 ml to 1600 ml. Total cell numbers fell markedly after both treatments, and tumor cells rose with disease progression and fell with partial response. In the five-patient comparison, patients 3 and 5 had no M2 macrophages in the fluid although their biopsies contained substantial amounts. Patients 1, 2 and 5 had high levels of CD8 T cells in the fluid while these were virtually absent in their biopsies. The authors concluded that effusion fluid should be considered a separate immune compartment from the tumor. Because of the limited number of patients, they called the study a proof-of-concept and stated that their proposed model has to be confirmed in larger patient groups.

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: Retrospective analysis of patient material; the authors call it a proof-of-concept study. It combined a one-patient follow-up over time with a five-patient comparison of pleural effusion and tumor biopsy.
• Who was studied: Five patients with malignant pleural mesothelioma of the epithelioid subtype, diagnosed by the Dutch National Mesothelioma Panel. Their tumor biopsies and pleural effusions were taken at the same time point during VATS biopsy, before any treatment. Material was collected between 2010 and 2013. One of the five patients had 10 effusion samples over one year.
• Exposure: Asbestos exposure was not studied. For the one patient followed over time, the article examined treatments: four courses of cisplatin and pemetrexed chemotherapy, then three courses of dendritic cell-based immunotherapy as maintenance, and talc pleurodesis attempts.
• Main results:
  • In the one patient who had 10 drainages over one year, the amount of pleural effusion drained varied between 400 ml and 1600 ml.
  • In that patient, the total number of cells in the effusion decreased markedly after chemotherapy and after immunotherapy.
  • In that patient, tumor cells (calretinin positive) in the effusion tracked clinical response: progression was associated with an increase and partial response with a decrease. The percentage was not affected after immunotherapy.
  • In that patient, T cells (CD3 positive) made up 3% to 20% of effusion cells over time. Their relative amount fell after both treatments, with no evident correlation with disease state.
  • In that patient, CD68 positive macrophages in the effusion were not influenced by treatment or disease state and were constantly high (data not shown).
  • In the five-patient comparison, patients 3 and 5 had no M2 macrophages (CD163) detected in the effusion, while their tumor biopsies contained a substantial amount.
  • In the five-patient comparison, patients 1, 2 and 5 had high levels of CD8 T cells in the effusion, but these cells were virtually absent in their tumor biopsies.
  • Across the five patients, M2 macrophages were mainly found in the tumor biopsies and CD8 T cells mainly in the effusions.
• The authors' conclusion: The authors concluded that the immune cells in the tumor may not be mirrored in the pleural effusion. They wrote that, to develop precision immunotherapy in mesothelioma, the effusion should be considered a separate immunological compartment from the pleural tumor.
• Limitations the authors state:
  • Because of the limited number of patients, the authors regard the study as a proof-of-concept for future studies.
  • The changes in immune cells over time came from a single patient and could not be explained from that one case.
  • No matched blood samples were available from the included patients.
  • The final effusion sample was taken after talc pleurodesis, and talc could have influenced the immune cells. The authors found no changes in T cell or macrophage amounts.
  • The authors' proposed model needs to be confirmed in larger groups of mesothelioma patients.

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: Immunotherapy, Pleural Effusion, Malignant Mesothelioma, Pleural Mesothelioma, Immunohistochemistry, Macrophage, Chemotherapy.

Related studies

• Immunotherapy strategies for mesothelioma - the role of tumor specific neoantigens in a new era of precision medicine — L. Ye, S. Ma, et al. (2019)
• Pleural Effusion of Patients with Malignant Mesothelioma Induces Macrophage-Mediated T Cell Suppression — L.A. Lievense, R. Cornelissen, et al. (2016)
• Dendritic cell-based immunotherapy in mesothelioma — R. Cornelissen, L.A. Lievense, et al. (2012)
• Is immunotherapy a viable option in treating mesothelioma? — D.W. Dumoulin, J.G. Aerts, et al. (2017)
• Tumor-associated macrophages in thoracic malignancies — L.A. Lievense, K. Bezemer, et al. (2013)
• New roads open up for implementing immunotherapy in mesothelioma — R. Cornelissen, M.E. Heuvers, et al. (2012)

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