{"title":"接受免疫治疗的胸膜间皮瘤患者的预后免疫炎症和转录组学特征。","authors":"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","doi":"10.1080/1750743X.2025.2549240","DOIUrl":null,"url":null,"abstract":"<p><strong>Aim: </strong>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).</p><p><strong>Methods: </strong>Advanced PM patients (<i>n</i> = 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.</p><p><strong>Results: </strong>Higher baseline CD4<sup>+</sup> GnzB<sup>+</sup> T cells were significantly associated with OS ≥ 12 months (<i>p</i> < 0.001), PFS ≥ 6 months (<i>p</i> = 0.027), and TTF ≥ 6 months (<i>p</i> = 0.016), along with lower CD14<sup>+</sup> monocytes (PFS: <i>p</i> = 0.038). Elevated proliferating CD8<sup>+</sup> Ki67<sup>+</sup> T cells (PFS: <i>p</i> = 0.038; TTF: <i>p</i> = 0.022) also predicted improved outcomes. Low IL-2 levels correlated with OS ≥ 12 months (<i>p</i> = 0.02). TIME analysis showed higher intratumor CD4<sup>+</sup> TILs (<i>p</i> = 0.03) and CD4/CD8 ratio (<i>p</i> = 0.016) in long survivors. Transcriptomics revealed nine genes differentially regulated according to clinical outcomes, among which <i>ULBP2</i> emerged as a strong predictor of poor prognosis (LASSO-Cox regression model).</p><p><strong>Conclusion: </strong>Parallel immune and transcriptomic profiling identifies biomarkers predictive of IT benefit in PM.</p>","PeriodicalId":13328,"journal":{"name":"Immunotherapy","volume":" ","pages":"879-890"},"PeriodicalIF":2.3000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439584/pdf/","citationCount":"0","resultStr":"{\"title\":\"Prognostic immunoinflammatory and transcriptomic profiles in patients with pleural mesothelioma undergoing immunotherapy.\",\"authors\":\"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\",\"doi\":\"10.1080/1750743X.2025.2549240\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aim: </strong>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).</p><p><strong>Methods: </strong>Advanced PM patients (<i>n</i> = 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.</p><p><strong>Results: </strong>Higher baseline CD4<sup>+</sup> GnzB<sup>+</sup> T cells were significantly associated with OS ≥ 12 months (<i>p</i> < 0.001), PFS ≥ 6 months (<i>p</i> = 0.027), and TTF ≥ 6 months (<i>p</i> = 0.016), along with lower CD14<sup>+</sup> monocytes (PFS: <i>p</i> = 0.038). Elevated proliferating CD8<sup>+</sup> Ki67<sup>+</sup> T cells (PFS: <i>p</i> = 0.038; TTF: <i>p</i> = 0.022) also predicted improved outcomes. Low IL-2 levels correlated with OS ≥ 12 months (<i>p</i> = 0.02). TIME analysis showed higher intratumor CD4<sup>+</sup> TILs (<i>p</i> = 0.03) and CD4/CD8 ratio (<i>p</i> = 0.016) in long survivors. Transcriptomics revealed nine genes differentially regulated according to clinical outcomes, among which <i>ULBP2</i> emerged as a strong predictor of poor prognosis (LASSO-Cox regression model).</p><p><strong>Conclusion: </strong>Parallel immune and transcriptomic profiling identifies biomarkers predictive of IT benefit in PM.</p>\",\"PeriodicalId\":13328,\"journal\":{\"name\":\"Immunotherapy\",\"volume\":\" \",\"pages\":\"879-890\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439584/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/1750743X.2025.2549240\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/8/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/1750743X.2025.2549240","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/20 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：采用翻译多尺度方法，包括肿瘤免疫微环境（TIME）、循环免疫炎症基准和转录组学特征，以确定晚期胸膜间皮瘤（PM）患者免疫治疗（IT）疗效的预后生物标志物。方法：接受纳武单抗联合伊匹单抗治疗的晚期PM患者（n = 17）被前瞻性纳入FIL-QI 2021研究。通过流式细胞术分析基线血液和肿瘤样本的免疫亚群和功能标志物（颗粒酶B， Ki67），多重ELISA分析细胞因子，免疫组织化学分析TILs和PD-L1，纳米链分析基因表达。评估与总生存期（OS）、无进展生存期（PFS）、治疗失败时间（TTF）和改良疾病控制率（mDCR）的关系。结果：基线CD4+ GnzB+ T细胞升高与OS≥12个月（p p = 0.027）和TTF≥6个月（p = 0.016）以及CD14+单核细胞降低（PFS: p = 0.038）显著相关。增殖性升高的CD8+ Ki67+ T细胞（PFS: p = 0.038; TTF: p = 0.022）也预示着预后的改善。IL-2水平低与OS≥12个月相关（p = 0.02）。时间分析显示，长期存活者肿瘤内CD4+ TILs （p = 0.03）和CD4/CD8比值（p = 0.016）较高。转录组学揭示了9个不同临床结局的基因差异调控，其中ULBP2是不良预后的重要预测因子（LASSO-Cox回归模型）。结论：平行免疫和转录组分析确定了PM中预测IT益处的生物标志物。
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.
期刊介绍：
Many aspects of the immune system and mechanisms of immunomodulatory therapies remain to be elucidated in order to exploit fully the emerging opportunities. Those involved in the research and clinical applications of immunotherapy are challenged by the huge and intricate volumes of knowledge arising from this fast-evolving field. The journal Immunotherapy offers the scientific community an interdisciplinary forum, providing them with information on the most recent advances of various aspects of immunotherapies, in a concise format to aid navigation of this complex field.
Immunotherapy delivers essential information in concise, at-a-glance article formats. Key advances in the field are reported and analyzed by international experts, providing an authoritative but accessible forum for this vitally important area of research. Unsolicited article proposals are welcomed and authors are required to comply fully with the journal''s Disclosure & Conflict of Interest Policy as well as major publishing guidelines, including ICMJE and GPP3.
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