Abstract
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.
Highlights
Malignant pleural mesothelioma (MPM) is a highly aggressive and fatal cancer that is most commonly associated with asbestos exposure [1]
Since expression of programmed death-1 (PD-1), T cell immunoglobulin mucin-3 (TIM-3) and lymphocyte activation gene-3 (LAG-3) has been reported on activated immune cells [26, 50, 51], stimulation of these cells will result in an increased expression on all three cell types. This idea is supported by the positive correlations that we found between CD69 and PD-1 expression and between CD69 and TIM-3 expression on CD8+ T cells
We show a patient-dependent inter- and intraspecific variation for both the immune cell composition and immune checkpoint expression in pleural versus ascites MPM effusions
Summary
Malignant pleural mesothelioma (MPM) is a highly aggressive and fatal cancer that is most commonly associated with asbestos exposure [1]. Due to differences in asbestos contact, MPM incidence varies between and within countries [2] It used to be a rare disease, its incidence has been increasing www.impactjournals.com/oncotarget in recent years and it is expected to continue in the decades. Palliative platinum-antifolate chemotherapy has a significant but limited impact on patients’ outcome with a median overall survival of about one year [4, 5]. Based on this poor prognosis and the increasing incidence, novel therapeutic strategies for MPM are urgently required
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