James Nicole E, Miller Katherine, LaFranzo Natalie, Lips Erin, Woodman Morgan, Ou Joyce, Ribeiro Jennifer R
Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI, United States.
Department of Obstetrics and Gynecology, Warren-Alpert Medical School of Brown University, Providence, RI, United States.
Front Oncol. 2021 Mar 5;11:622182. doi: 10.3389/fonc.2021.622182. eCollection 2021.
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide, as patients are typically diagnosed at a late stage and eventually develop chemoresistant disease following front-line platinum-taxane based therapy. Only modest results have been achieved with PD-1 based immunotherapy in ovarian cancer patients, despite the fact that immunological responses are observed in EOC patients. Therefore, the goal of this present study was to identify novel immune response genes and cell subsets significantly associated with improved high grade serous ovarian cancer (HGSOC) patient prognosis. A transcriptomic-based immune modeling analysis was employed to determine levels of 8 immune cell subsets, 10 immune escape genes, and 22 co-inhibitory/co-stimulatory molecules in 26 HGSOC tumors. Multidimensional immune profiling analysis revealed CTLA-4, LAG-3, and T as predictive for improved progression-free survival (PFS). Furthermore, the co-stimulatory receptor ICOS was also found to be significantly increased in patients with a longer PFS and positively correlated with levels of CTLA-4, PD-1, and infiltration of immune cell subsets. Both ICOS and LAG-3 were found to be significantly associated with improved overall survival in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Finally, PVRL2 was identified as the most highly expressed transcript in our analysis, with immunohistochemistry results confirming its overexpression in HGSOC samples compared to normal/benign. Results were corroborated by parallel analyses of TCGA data. Overall, this multidimensional immune modeling analysis uncovers important prognostic immune factors that improve our understanding of the unique immune microenvironment of ovarian cancer.
上皮性卵巢癌（EOC）是全球最致命的妇科恶性肿瘤，因为患者通常在晚期才被诊断出来，并且在一线铂类-紫杉烷类治疗后最终会发展为化疗耐药性疾病。尽管在EOC患者中观察到免疫反应，但基于PD-1的免疫疗法在卵巢癌患者中仅取得了有限的成果。因此，本研究的目的是确定与高级别浆液性卵巢癌（HGSOC）患者预后改善显著相关的新型免疫反应基因和细胞亚群。采用基于转录组的免疫建模分析来确定26个HGSOC肿瘤中8种免疫细胞亚群、10种免疫逃逸基因和22种共抑制/共刺激分子的水平。多维免疫谱分析显示，CTLA-4、LAG-3和T可预测无进展生存期（PFS）的改善。此外，还发现共刺激受体ICOS在PFS较长的患者中也显著增加，并且与CTLA-4、PD-1水平以及免疫细胞亚群的浸润呈正相关。在癌症基因组图谱（TCGA）卵巢癌队列中，发现ICOS和LAG-3均与总生存期的改善显著相关。最后，在我们的分析中，PVRL2被确定为表达最高的转录本，免疫组织化学结果证实其在HGSOC样本中的表达高于正常/良性样本。TCGA数据的平行分析证实了结果。总体而言，这种多维免疫建模分析揭示了重要的预后免疫因素，增进了我们对卵巢癌独特免疫微环境的理解。
