Mazzaschi Giulia, Rosati Roberto, D'Agnelli Simona, Minari Roberta, Trentini Francesca, Tamarozzi Prisca, Manini Martina, Zinelli Ronzoni Martina, Dodi Alessandra, Gnetti Letizia, Bottarelli Lorena, Azzoni Cinzia, Martines Gianmarco, Pluchino Monica, Toscani Ilaria, Leonetti Alessandro, Perrone Fabiana, Bordi Paola, Bocchialini Giovanni, Ampollini Luca, Quaini Federico, Tiseo Marcello
Department of Medicine and Surgery, University of Parma, Parma, Italy.
Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
Immunotherapy. 2025 Aug;17(12):879-890. doi: 10.1080/1750743X.2025.2549240. Epub 2025 Aug 20.
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).
Advanced PM patients ( = 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.
Higher baseline CD4 GnzB T cells were significantly associated with OS ≥ 12 months ( < 0.001), PFS ≥ 6 months ( = 0.027), and TTF ≥ 6 months ( = 0.016), along with lower CD14 monocytes (PFS: = 0.038). Elevated proliferating CD8 Ki67 T cells (PFS: = 0.038; TTF: = 0.022) also predicted improved outcomes. Low IL-2 levels correlated with OS ≥ 12 months ( = 0.02). TIME analysis showed higher intratumor CD4 TILs ( = 0.03) and CD4/CD8 ratio ( = 0.016) in long survivors. Transcriptomics revealed nine genes differentially regulated according to clinical outcomes, among which emerged as a strong predictor of poor prognosis (LASSO-Cox regression model).
Parallel immune and transcriptomic profiling identifies biomarkers predictive of IT benefit in PM.
采用一种涵盖肿瘤免疫微环境（TIME）、循环免疫炎症指标和转录组谱的转化性多尺度方法，以识别晚期胸膜间皮瘤（PM）患者免疫治疗（IT）疗效的预后生物标志物。
接受纳武单抗加伊匹单抗治疗的晚期PM患者（n = 17）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中的免疫亚群和功能标志物（颗粒酶B、Ki67），通过多重ELISA分析细胞因子，通过免疫组织化学分析肿瘤浸润淋巴细胞（TILs）和程序性死亡受体配体1（PD-L1），并通过纳米串分析基因表达。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）的相关性。
较高的基线CD4颗粒酶B T细胞与OS≥12个月（P < 0.001）、PFS≥6个月（P = 0.027）和TTF≥6个月（P = 0.016）显著相关，同时较低的CD14单核细胞也与之相关（PFS：P = 0.038）。增殖性CD8 Ki67 T细胞升高（PFS：P = 0.038；TTF：P = 0.022）也预示着预后改善。低白细胞介素-2水平与OS≥12个月相关（P = 0.02）。TIME分析显示，长期生存者的肿瘤内CD4 TILs较高（P = 0.03）和CD4/CD8比值较高（P = 0.016）。转录组学显示有9个基因根据临床结果存在差异调节，其中一个基因成为预后不良的强预测因子（套索-考克斯回归模型）。
并行的免疫和转录组分析确定了预测PM患者IT获益的生物标志物。
