Potential diagnostic and prognostic role of micro-environment in malignant pleural mesothelioma

Introduction. A comprehensive analysis of the immune-cell infiltrate collected from pleural fluid and from biopsies of malignant pleural mesothelioma (MPM) may contribute to understand the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Till now such approach has not routinely been verified. Methods. We enrolled in 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsies used for the pathological diagnosis and the immune-phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed by Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune-phenotype data with patients’ outcome. Results. The cut-offs of intra-tumor T-regulatory (Treg; >1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4+PD1+ (>5.2%) and CD8+PD1+ (6.4%) cells, CD4+LAG3+ (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+TIM-3+ (>2.5%) and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intra-tumor MDSC contributed to the anergy of tumorinfiltrating lymphocytes (TILs). The immune-phenotype of pleural fluid cells had no prognostic significance. By contrast, the intra-tumor Treg and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+TILs correlated with overall survival. Conclusions. A clear immune-signature of pleural fluids and tissues of MPM patients may contribute to better predict patients’ outcome.