Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients
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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
Elly Marcq, email: Elly.Marcq@uantwerpen.be
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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