Research Papers:

Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients

Elly Marcq _, Jorrit De Waele, Jonas Van Audenaerde, Eva Lion, Eva Santermans, Niel Hens, Patrick Pauwels, Jan P. van Meerbeeck and Evelien L.J. Smits

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Oncotarget. 2017; 8:89722-89735. https://doi.org/10.18632/oncotarget.21113

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Elly Marcq1, Jorrit De Waele1, Jonas Van Audenaerde1, Eva Lion2, Eva Santermans3, Niel Hens3,4, Patrick Pauwels1,5, Jan P. van Meerbeeck1,6,* and Evelien L.J. Smits1,2,*

1Center for Oncological Research, University of Antwerp, Antwerp, Belgium

2Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium

3Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Diepenbeek, Belgium

4Center for Health Economics Research and Modelling Infectious Diseases, University of Antwerp, Antwerp, Belgium

5Department of Pathology, Antwerp University Hospital, Antwerp, Belgium

6Thoracic Oncology/MOCA, Antwerp University Hospital, Antwerp, Belgium

*Shared senior authors

Correspondence to:

Elly Marcq, email: [email protected]

Keywords: mesothelioma, immune checkpoints, effusions, tumor microenvironment, flow cytometry

Received: April 21, 2017     Accepted: September 01, 2017     Published: September 21, 2017


Malignant pleural mesothelioma (MPM) is an aggressive cancer with an increasing incidence, poor prognosis and limited effective treatment options. Hence, new treatment strategies are warranted which include immune checkpoint blockade approaches with encouraging preliminary data. Research on the immunological aspects of the easily accessible mesothelioma microenvironment could identify prognostic and/or predictive biomarkers and provide useful insights for developing effective immunotherapy.

In this context, we investigated the immune cell composition of effusions (pleural and ascites fluids) from 11 different chemotherapy-treated MPM patients. We used multicolor flow cytometry to describe different subsets of immune cells and their expression of immune checkpoint molecules TIM-3, LAG-3, PD-1 and PD-L1. We demonstrate a patient-dependent inter- and intraspecific variation comparing pleural and ascites fluids in immune cell composition and immune checkpoint expression. We found CD4+ and CD8+ T cells, B cells, macrophages, natural killer cells, dendritic cells and tumor cells in the fluids. To the best of our knowledge, we are the first to report TIM-3 and LAG-3 expression and we confirm PD-1 and PD-L1 expression on different MPM effusion-resident immune cells. Moreover, we identified two MPM effusion-related factors with clinical value: CD4+ T cells were significantly correlated with better response to chemotherapy, while the percentage of PD-L1+ podoplanin (PDPN)+ tumor cells is a significant prognostic factor for worse outcome. Our data provide a basis for more elaborate research on MPM effusion material in the context of treatment follow-up and prognostic biomarkers and the development of immune checkpoint-targeted immunotherapy.

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