Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified.

We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients' outcome.

The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule-positive (CD4⁺) programmed death 1-positive (PD-1⁺) (>5.2%) and CD8⁺PD-1⁺ (6.4%) cells, CD4⁺ lymphocyte activating 3-positive (LAG-3⁺) (>2.8% ) and CD8⁺LAG-3⁺ (>2.8%) cells, CD4⁺ T cell immunoglobulin and mucin domain 3-positive (TIM-3⁺) (>2.5%), and CD8⁺TIM-3⁺ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1⁺/LAG-3⁺/TIM-3⁺ CD4⁺ tumor-infiltrating lymphocytes correlated with overall survival.

A clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients' outcome.