bims-mesote 2025-08-31 papers

Issue of 2025–08–31
three papers selected by
Laura Mannarino, Humanitas Research

Immunotherapy. 2025 Aug 20. 1-12

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

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

DOI: https://doi.org/10.1080/1750743X.2025.2549240

Respirol Case Rep. 2025 Aug;13(8): e70297

Partial Response to Nivolumab and Ipilimumab in a Patient With Malignant Pleural Mesothelioma and Pre-Existing Myasthenia Gravis Without Severe Flares or Immune-Related Adverse Events: A Case Report.

Mariko Higa, Tomoya Kuda, Yuichiro Ohya, Hidenori Kawasaki.

Detailed clinical data on the combination immune checkpoint inhibitor (ICI) therapy in patients with myasthenia gravis (MG) remain limited. We report a case of malignant pleural mesothelioma with previously undiagnosed ocular MG. Owing to hepatic dysfunction, reduced doses of nivolumab and ipilimumab were administered before confirmation of anti-acetylcholine receptor (AChR) antibody positivity. MG was diagnosed based on subtle ocular symptoms and serological tests. Prophylactic intravenous immunoglobulin and an acetylcholinesterase inhibitor were administered; combination therapy was discontinued owing to the risk of MG flare, but a partial tumour response was achieved. With disease progression, nivolumab monotherapy was reintroduced, and early steroid pulse therapy was administered owing to elevated creatine kinase, again inducing a partial response. Serological screening for anti-AChR antibodies may help prevent severe MG flares and immune-related adverse events. With caution, dose-reduced and limited-exposure ICI combination therapy may be feasible in selected patients with MG under appropriate prophylactic management.

Keywords: disease flares; immune‐related adverse events; ipilimumab; nivolumab; pre‐existing myasthenia gravis

DOI: https://doi.org/10.1002/rcr2.70297

Genes Genomics. 2025 Aug 25.

Multi-omics integration reveals CYTL1 and H6PD as key regulators of tumor metabolism in mesothelioma.

Jiao Ma, Huilin Zhang, Luanxue Yu, Yunqing Guo, Jiawei Ming, Zhenying Guo.

BACKGROUND: Mesothelioma is a rare and aggressive cancer with limited therapeutic options and poor prognosis. Despite advancements in understanding its molecular mechanisms, effective biomarkers and therapeutic targets remain elusive.
OBJECTIVE: This study utilizes a multi-omics approach to identify potential biomarkers and therapeutic targets for mesothelioma.
METHODS: A multi-omics framework integrating druggable genomics, Mendelian randomization (MR), and single-cell RNA sequencing (scRNA-seq) was employed. Druggable genes were identified using expression quantitative trait loci data, and therapeutic targets were predicted through MR analysis. These targets were cross-referenced with mesothelioma-specific single-cell markers and validated by summary data-based MR and protein quantitative trait loci analysis. Gene Ontology, KEGG, and Gene Set Enrichment Analysis were used to explore functional mechanisms. Drug sensitivity was assessed with the GDSC2 dataset, and potential therapeutic compounds were identified through molecular docking simulations using the Drug Signature Database. Mediated MR analysis investigated 731 immune cells and 1,400 metabolites as mediators of the identified genes' effects on mesothelioma.
RESULTS: CYTL1 and H6PD were identified as potential biomarkers and therapeutic targets for mesothelioma. CYTL1 was associated with poor prognosis and reduced drug sensitivity, while H6PD showed the opposite trend. Although molecular docking results for H6PD were unfavorable, compounds targeting CYTL1 were identified. Immune cells did not mediate the effects of either gene on mesothelioma progression, despite their prognostic associations. Metabolic mediation analysis revealed that CYTL1 influences mesothelioma via levulinoylcarnitine levels, whereas H6PD regulates tumor metabolism through the mannose-to-mannitol-to-sorbitol ratio and glutamate-to-5-oxoproline ratio.
CONCLUSION: This study identifies CYTL1 and H6PD as key regulators of tumor metabolism in mesothelioma. CYTL1 is a promising therapeutic target, warranting further investigation, while H6PD remains a potential candidate despite unfavorable docking results. These findings demonstrate the value of multi-omics approaches in identifying novel therapeutic targets for mesothelioma.

Keywords: CYTL1; H6PD; MR; Mesothelioma; Metabolism; scRNA-seq

DOI: https://doi.org/10.1007/s13258-025-01667-2