PO.TB10.09 · 肿瘤生物学
雌二醇响应性微龛驱动肿瘤微环境中的免疫排斥
Estradiol-responsive niches drive immune exclusion in the tumor microenvironment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
上皮性卵巢癌（EOC）表现出显著的分子多样性，这在很大程度上受肿瘤微环境（TME）影响。然而，驱动这种多样性的具体因素仍不明确。我们建立了一个多组学平台，将生长因子组学分析与患者来源的卵巢肿瘤组织的转录组分析相整合。利用来自31例EOC患者的样本，我们鉴定了128种因子组合的响应性，并通过整合的批量（bulk）和单细胞RNA测序进行分析。我们鉴定出两个主要簇，一个对雌二醇和Wnt响应，另一个对R-spondin响应。这些结果进一步通过对涵盖33种癌症类型的11,000例TCGA肿瘤的泛癌分析得到验证，证实了该响应程序的保守性和临床相关性。雌二醇暴露诱导了以间充质和干细胞相关转录特征为特点的强劲增殖，从而导致肿瘤生长。单细胞分析鉴定出两个雌二醇响应性微龛：一个恶性PDCD5+亚型和一个表达TNFSF10的成纤维细胞群体，两者在雌二醇刺激后均增加。MAL.PDCD5细胞表现出抗原呈递受损以及通过降低氧化磷酸化实现的代谢抑制，而FB.TNFSF10成纤维细胞则表现出TGF-beta和CAF.S1信号增强，与免疫抑制性重编程一致。空间转录组分析揭示了FB.TNFSF10成纤维细胞与T/NK细胞之间明显的空间隔离，为激素诱导的免疫排斥提供了直接证据。在多种肿瘤类型中，FB.TNFSF10表达升高与基质细胞和调节性T细胞评分升高相关，并且是免疫检查点阻断响应降低的独立预测因子，独立于PD-L1表达或肿瘤突变负荷。这些发现证明存在一个保守的雌二醇响应性结构，它重塑肿瘤微环境，阻止免疫浸润。这些发现提示了可能提高多种癌症免疫治疗疗效的新型生物标志物和治疗靶点。
查看英文原文 English abstract
Epithelial ovarian cancer (EOC) presents marked molecular diversity, which is largely influenced by the tumor microenvironment (TME). However, the specific factors driving this diversity remain unclear. We established a multi-omics platform integrating growth factor-omics profiling with transcriptomic analysis of patient-derived ovarian tumor tissues. Using samples from 31 EOC patients, we identified the responsiveness of 128 factor combinations and analyzed through integrated bulk and single-cell RNA sequencing. Two main clusters were identified, one responsive to estradiol and Wnt and the other to R-spondin. These results were further validated by a pan-cancer analysis of 11,000 TCGA tumors across 33 cancer types, confirming the conservativeness and clinical relevance of this response program. Estradiol exposure induced robust proliferation characterized by mesenchymal and stem cell-associated transcriptional signatures, leading to tumor growth. Single-cell analysis identified two estradiol-responsive niches: a malignant PDCD5+ subtype and a TNFSF10-expressing fibroblast population, both of which increased after estradiol stimulation. MAL.PDCD5 cells exhibited impaired antigen presentation and metabolic suppression via reduced oxidative phosphorylation, whereas FB.TNFSF10 fibroblasts exhibited increased TGF-beta and CAF.S1 signaling, consistent with immunosuppressive reprogramming. Spatial transcriptomic analysis revealed a distinct spatial segregation between FB.TNFSF10 fibroblasts and T/NK cells, providing direct evidence for hormone-induced immune exclusion. Across various tumor types, elevated FB.TNFSF10 expression correlated with elevated stromal cell and regulatory T cell scores and was an independent predictor of reduced response to immune checkpoint blockade, independent of PD-L1 expression or tumor mutation burden. These findings demonstrate a preserved estradiol-responsive architecture that remodels the tumor microenvironment, preventing immune infiltration. These findings suggest novel biomarkers and therapeutic targets that could enhance the efficacy of immunotherapy across diverse cancers.
利益披露 Disclosure
M. Kim, None..
K. Lee, None..
H. Kang, None..
J. Lee, None.