Prognostic immunoinflammatory and transcriptomic profiles in patients with pleural mesothelioma undergoing immunotherapy
Immunotherapy 2025 August 20 [Link]
Giulia Mazzaschi, Roberto Rosati, Simona D’Agnelli, Roberta Minari, Francesca Trentini, Prisca Tamarozzi, Martina Manini, Martina Zinelli Ronzoni, Alessandra Dodi, Letizia Gnetti, Lorena Bottarelli, Cinzia Azzoni, Gianmarco Martines, Monica Pluchino, Ilaria Toscani, Alessandro Leonetti, Fabiana Perrone, Paola Bordi, Giovanni Bocchialini, Luca Ampollini, Federico Quaini, Marcello Tiseo
Abstract
Aim: A translational multiscale approach, encompassing tumor immune microenvironment (TIME), circulating immune-inflammatory benchmarks, and transcriptomic profiles, was undertaken to identify prognostic biomarkers of immunotherapy (IT) efficacy in patients with advanced pleural mesothelioma (PM).
Methods: Advanced PM patients (n = 17) treated with nivolumab plus ipilimumab were prospectively enrolled in the FIL-QI 2021 study. Baseline blood and tumor samples were analyzed for immune subsets and functional markers (Granzyme B, Ki67) by flow cytometry, cytokines by multiplex ELISA, TILs and PD-L1 by immunohistochemistry, and gene expression by nanostring. Associations with overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), and modified disease control rate (mDCR) were assessed.
Results: Higher baseline CD4+ GnzB+ T cells were significantly associated with OS ≥ 12 months (p < 0.001), PFS ≥ 6 months (p = 0.027), and TTF ≥ 6 months (p = 0.016), along with lower CD14+ monocytes (PFS: p = 0.038). Elevated proliferating CD8+ Ki67+ T cells (PFS: p = 0.038; TTF: p = 0.022) also predicted improved outcomes. Low IL-2 levels correlated with OS ≥ 12 months (p = 0.02). TIME analysis showed higher intratumor CD4+ TILs (p = 0.03) and CD4/CD8 ratio (p = 0.016) in long survivors. Transcriptomics revealed nine genes differentially regulated according to clinical outcomes, among which ULBP2 emerged as a strong predictor of poor prognosis (LASSO-Cox regression model).
Conclusion: Parallel immune and transcriptomic profiling identifies biomarkers predictive of IT benefit in PM.
