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. 2025 Aug;17(12):879-890.
doi: 10.1080/1750743X.2025.2549240. Epub 2025 Aug 20.

Prognostic immunoinflammatory and transcriptomic profiles in patients with pleural mesothelioma undergoing immunotherapy

Giulia Mazzaschi  1   2 , Roberto Rosati  1 , Simona D'Agnelli  2 , Roberta Minari  2 , Francesca Trentini  1   2 , Prisca Tamarozzi  1   2 , Martina Manini  1   2 , Martina Zinelli Ronzoni  1   2 , Alessandra Dodi  2 , Letizia Gnetti  3 , Lorena Bottarelli  1 , Cinzia Azzoni  1 , Gianmarco Martines  2 , Monica Pluchino  2 , Ilaria Toscani  4 , Alessandro Leonetti  2 , Fabiana Perrone  2 , Paola Bordi  2 , Giovanni Bocchialini  5 , Luca Ampollini  1   5 , Federico Quaini  1 , Marcello Tiseo  1   2
Affiliations

Prognostic immunoinflammatory and transcriptomic profiles in patients with pleural mesothelioma undergoing immunotherapy

Giulia Mazzaschi et al. Immunotherapy. 2025 Aug.

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.

Keywords: CD4+ T cells; Immunotherapy; Pleural mesothelioma; biomarkers; granzyme B; peripheral blood immunophenotyping; transcriptomics; tumor immune microenvironment.

Plain language summary

Understanding who benefits from immunotherapy in pleural mesotheliomaPleural mesothelioma (PM) is a rare and aggressive cancer linked to asbestos exposure. Immunotherapy, specifically a combination of two drugs, nivolumab and ipilimumab, has improved survival for some patients, but it is still unclear why only certain individuals respond well. In this study, researchers aimed to understand which biological features might predict better outcomes. They studied patients with advanced PM who were treated with immunotherapy as part of a multicentre clinical study. Before treatment, they collected blood and tumor samples and analyzed them using several laboratory techniques. They looked at immune cells in the blood, molecules linked to inflammation, immune cells inside the tumor, and patterns of gene activity (called transcriptomics). They found that patients who lived longer or responded better to treatment had higher levels of specific “active” immune cells in their blood – specifically, CD4+ T cells carrying proteins called Granzyme B and Ki67, which indicate the ability to kill tumor cells and to multiply. These patients also had lower levels of a protein called IL-2 and fewer CD14+ immune cells, which may contribute to “negative” inflammation. Inside the tumor, having more CD4+ immune cells and a higher ratio of CD4 to CD8 cells was also linked to better outcomes. Gene analysis suggested that ULBP2 negatively impact on patient prognosis. This study shows that combining blood and tumor immune-inflammatory profiles together with genetic information may help predict who benefits from immunotherapy – and could one day guide more personalized treatment for people with PM.

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Conflict of interest statement

Marcello Tiseo received speakers’ and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Takeda, Amgen, Merck, Sanofi, Johnson & Johnson, Pierre Fabre, Regeneron, BeiGene and Daiichi Sankyo. Marcello Tiseo received institutional research grants from Astra-Zeneca, Boehringer Ingelheim and Roche. Marcello Tiseo received travel support from Amgen, Takeda and Roche.

Alessandro Leonetti has received speaker’s fee for AstraZeneca, BMS, MSD, Regeneron, Sanofi and Takeda. Alessandro Leonetti has been on advisory board for AstraZeneca, BeiGene, Novartis and Sanofi. Alessandro Leonetti has received consultant’s fee for Amgen. Alessandro Leonetti has attended editorial activities sponsored by Eli Lilly, Novartis and Roche. Alessandro Leonetti has received travel support from MSD, Novartis, Roche and Takeda.

No writing assistance was utilized in the production of this manuscript.

References

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    2. •• This manuscript clearly documents the efficacy of dual immunotherapy given as first line in the treatment of pleural mesothelioma and establishes a new standard of care in this setting.

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    2. • This study was one of the first studies reporting the prognostic role of the immune microenvironment, both tumoral and stromal, in pleural mesothelioma.

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