title: Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a presumed role in the protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints can identify new immunotherapeutic targets and their predictive and/or prognostic value. To characterize the TME and the immune checkpoint expression profile, we performed immunohistochemistry (IHC) on formalin-fixed paraffin embedded (FFPE) tissue sections from 54 MPM patients (40 at time of diagnosis; 14 treated with chemotherapy). We stained for PD-1, PD-L1, TIM-3, LAG-3, CD4, CD8, CD45RO, granzyme B, FoxP3 and CD68. Furthermore, we analyzed the relationship between the immunological parameters and survival, as well as response to chemotherapy. We found that TIM-3, PD-1 and PD-L1 were expressed on both immune and tumor cells. Strikingly, PD-1 and PD-L1 expression on tumor cells was only seen in unpretreated samples. No LAG-3 expression was observed. CD45RO expression in the stroma was an independent negative predictive factor for response on chemotherapy, while CD4 and TIM-3 expression in lymphoid aggregates were independent prognostic factors for better outcome. Our data propose TIM-3 as a promising new target in mesothelioma. Chemotherapy influences the expression of immune checkpoints and therefore further research on the best combination treatment schedule is required.
authors.affiliation: Center for Oncological Research, University of Antwerp , Antwerp, Belgium.
authors.forename: Elly
authors.initials: E
authors.lastname: Marcq
authors.affiliation: Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Siozopoulou
authors.affiliation: Center for Oncological Research, University of Antwerp , Antwerp, Belgium.
authors.forename: Jorrit
authors.initials: J
authors.lastname: De Waele
authors.affiliation: Center for Oncological Research, University of Antwerp , Antwerp, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: van Audenaerde
authors.affiliation: Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Zwaenepoel
authors.affiliation: Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University , Diepenbeek, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Santermans
authors.affiliation: Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Diepenbeek, Belgium; Centre for Health Economics Research and Modeling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Niel
authors.initials: N
authors.lastname: Hens
authors.affiliation: Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.affiliation: Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Thoracic Oncology/MOCA, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Jan P
authors.initials: JP
authors.lastname: van Meerbeeck
authors.affiliation: Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Evelien L J
authors.initials: EL
authors.lastname: Smits
keywords: Biomarkers; immune checkpoints; immunohistochemistry; mesothelioma; tumor microenvironment