Ricciuti Jason, Liu Qian, Khan A N M Nazmul H, Joseph Janine M, Veuskens Bert, Giridharan Thejaswini, Suzuki Sora, Emmons Tiffany, Yaffe Michael, Kuijpers Taco W, Jongerius Ilse, Brouwer Mieke, Pouw Richard B, Odunsi Kunle, Frederick Peter, Mager Katherine LaVigne, Lele Shashikant, Gaulin Nicole, Hakim Christiane, Edwards Robert P, Olawaiye Alexander B, Sukamanovich Paniti, Taylor Sarah, Elishaev Esther, Zsiros Emese, Modugno Francesmary, Moysich Kirsten, Segal Brahm
Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States of America; Dr. Ricciuti is currently in the Division of Gynecologic Oncology, Saint Louis University School of Medicine, Saint Louis, MO, United States of America.
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States of America.
Gynecol Oncol. 2025 Feb;193:49-57. doi: 10.1016/j.ygyno.2024.12.006. Epub 2025 Jan 6.
We observed that the tumor microenvironment (TME) in metastatic epithelial ovarian cancer (EOC) and in other solid tumors can reprogram normal neutrophils to acquire a complement-dependent suppressor phenotype characterized by inhibition of stimulated T cell activation. This study aims to evaluate whether serum markers of neutrophil activation and complement at diagnosis of EOC would be associated with clinical outcomes.
We conducted a two-center prospective study of patients with newly diagnosed EOC (N = 188). Blood and ascites fluid were collected at diagnosis for biomarker analysis. Patients were evaluated for progression-free survival (PFS) and overall survival (OS).
The median OS was 47 months (95 % CI: 34-58) and the median PFS was 12 months (95 % CI: 11-15). Pre-treatment serum levels of genomic DNA (gDNA), markers of neutrophil degranulation (myeloperoxidase [MPO]) and neutrophil extracellular traps (NETs) (citrullinated histone H3 [CitH3]), and complement activation (C3b/c) were each associated with worse OS in univariate analysis. In multivariate analyses controlling for age, stage, and optimal debulking, serum gDNA, MPO, and CitH3 remained associated with worse OS, while C3b/c levels were not. In an exploratory analysis, the largest magnitude of difference in 2-year OS occurred in patients with low C3b/c and low CitH3 compared to all other patients (87 % vs 46 % survival, respectively). In ascites fluid, increased factor H, a negative regulator of complement activation, was associated with improved OS in univariate analysis.
These results point to serum gDNA, NETs, and complement activation as potential prognostic biomarkers in patients with newly diagnosed EOC.
我们观察到转移性上皮性卵巢癌（EOC）及其他实体瘤中的肿瘤微环境（TME）可使正常中性粒细胞重新编程，使其获得一种补体依赖性抑制表型，其特征为抑制受刺激的T细胞活化。本研究旨在评估EOC诊断时中性粒细胞活化和补体的血清标志物是否与临床结局相关。
我们对188例新诊断的EOC患者进行了一项两中心前瞻性研究。在诊断时采集血液和腹水进行生物标志物分析。对患者进行无进展生存期（PFS）和总生存期（OS）评估。
中位OS为47个月（95%CI：34 - 58），中位PFS为12个月（95%CI：11 - 15）。在单因素分析中，治疗前血清基因组DNA（gDNA）、中性粒细胞脱颗粒标志物（髓过氧化物酶[MPO]）和中性粒细胞胞外诱捕网（NETs）（瓜氨酸化组蛋白H3[CitH3]）以及补体激活（C3b/c）均与较差的OS相关。在多因素分析中，在控制年龄、分期和最佳肿瘤细胞减灭术的情况下，血清gDNA、MPO和CitH3仍与较差的OS相关，而C3b/c水平则不然。在一项探索性分析中，与所有其他患者相比，C3b/c和CitH3水平低的患者2年OS差异最大（分别为87%和46%生存率）。在腹水中，补体激活的负调节因子H因子增加与单因素分析中较好的OS相关。
这些结果表明血清gDNA、NETs和补体激活是新诊断EOC患者潜在的预后生物标志物。
