Laga T, Van Rompuy A S, Busschaert P, Marquina G, Loverix L, Olbrecht S, Ottenbourgs T, Baert T, Van Gorp T, Vergote I, Lambrechts D, Van Nieuwenhuysen E
Department of Gynaecological Oncology, University Hospital Leuven, Leuven, Belgium.
Laboratory of Gynaecological Oncology, KU Leuven, Leuven, Belgium.
Br J Cancer. 2025 Apr 23. doi: 10.1038/s41416-025-03012-6.
BACKGROUND: The tumour microenvironment of rare ovarian germ cell tumours (OGCT) and sex-cord stromal tumours (SCST) remains unexplored. To better understand their immune and stromal landscape, we constructed a blueprint using single-cell RNA sequencing (scRNA-seq). METHODS: We performed scRNA-seq of 66, 919 cells from twelve fresh tumour samples: seven adult granulosa cell tumour (aGSCT), one juvenile GSCT (jGSCT), one Sertoli-Leydig (SL) tumour, two immature teratoma (IT) and one dysgerminoma (DG). We characterised immune cell subtypes and fibroblasts based on their specific marker genes. Validation included combined positive score (CPS) of 46 OGCTs and 66 SCSTs, and bulk RNA sequencing (n = 32). RESULTS: Cell clustering and annotation revealed a immune-activated microenvironment in DG, driven by PD-1- exhausted T cells, reflected in high CPS (≥10) and upregulated immune pathways. IT samples displayed no immunoreactive profile, consistent with a negative CPS. aGSCTs exhibited a fibroblast-enriched, immune-desert phenotype, with low T cell infiltration and increased immunosuppressive LYVE1 and CX3CR1+ macrophages, corresponding to negative CPS. CONCLUSION: We constructed a detailed blueprint of the OGCT and SCSTs microenvironment of, elucidating potential modulators that shape their immune landscape. The immune-suppressive environment in aGSCTs likely limits immunotherapy response, as immunosuppressive macrophages inhibit T cell expansion along with EMT activation and fibroblast predominance.
背景:罕见卵巢生殖细胞肿瘤(OGCT)和性索间质肿瘤(SCST)的肿瘤微环境仍未得到充分研究。为了更好地了解它们的免疫和基质情况,我们利用单细胞RNA测序(scRNA-seq)构建了一个蓝图。 方法:我们对来自12个新鲜肿瘤样本的66919个细胞进行了scRNA-seq,这些样本包括7例成人颗粒细胞瘤(aGSCT)、1例青少年颗粒细胞瘤(jGSCT)、1例支持-间质细胞瘤(SL)、2例未成熟畸胎瘤(IT)和1例无性细胞瘤(DG)。我们根据免疫细胞亚型和成纤维细胞的特异性标记基因对其进行了表征。验证包括46例OGCT和66例SCST的联合阳性评分(CPS),以及批量RNA测序(n = 32)。 结果:细胞聚类和注释显示,DG中存在由PD-1耗竭T细胞驱动的免疫激活微环境,这在高CPS(≥10)和上调的免疫途径中得到体现。IT样本未显示免疫反应性特征,与阴性CPS一致。aGSCT表现出富含成纤维细胞的免疫荒漠表型,T细胞浸润低,免疫抑制性LYVE1和CX3CR1 +巨噬细胞增加,对应阴性CPS。 结论:我们构建了OGCT和SCST微环境的详细蓝图,阐明了塑造其免疫格局的潜在调节因子。aGSCT中的免疫抑制环境可能会限制免疫治疗反应,因为免疫抑制性巨噬细胞会抑制T细胞扩增,同时激活EMT和成纤维细胞占主导地位。
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