PO.ET01.01 · 实验与分子治疗
组织因子表达与卵巢透明细胞癌中B7-H4介导的免疫逃逸相关,并与临床前模型中对tisotumab vedotin的应答相关
Tissue Factor expression is associated with B7-H4-mediated immune evasion in ovarian clear cell carcinoma and with response to tisotumab vedotin in preclinical models
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摘要 Abstract
中文摘要
目的:卵巢透明细胞癌(OCCC)特征性地过表达组织因子(TF;F3),但其生物学意义和治疗意义仍不明确。我们旨在阐明TF表达在OCCC中的影响,并在体外和体内模型中评估抗TF抗体-药物偶联物tisotumab vedotin(TV)的抗肿瘤疗效。
方法:我们对112例临床OCCC病例进行了批量RNA测序(RNA-seq),以鉴定F3高表达肿瘤的转录组特征。随后我们对3例F3高表达和3例F3低表达病例应用单核RNA测序(snRNA-seq),以在单细胞水平表征肿瘤生物学。基于这些转录组结果,我们聚焦于免疫相关通路和免疫检查点分子,重点关注VTCN1(B7-H4)。对57例OCCC标本进行了TF和B7-H4的免疫组织化学分析。最后,我们在患者来源的OCCC球体和异种移植中评估了TV的活性。
结果:在批量RNA-seq中,F3高表达肿瘤表现出较低的免疫评分,伴随MYC和细胞周期通路的上调,以及炎症和免疫通路的抑制。一致地,snRNA-seq在癌细胞中显示出类似趋势,且F3高表达肿瘤的免疫细胞比例显著降低,表明其处于免疫学上的“冷”状态。值得注意的是,免疫检查点分子VTCN1在F3高表达肿瘤中高表达,并与F3表达呈正相关。免疫组织化学证实B7-H4在TF阳性肿瘤中显著过表达,显示TF与B7-H4表达之间呈正相关。TV活性在体外与TF丰度相关,并在F3高表达异种移植中诱导显著的生长抑制;残余肿瘤显示TF和B7-H4表达降低。
结论:TF高表达OCCC显示出独特的基因表达模式,尤其是伴有B7-H4介导免疫逃逸的免疫学“冷”亚型。TV表现出TF依赖性活性,支持TF作为治疗靶点,并为OCCC中基于TV的单药治疗或与免疫治疗联合提供了理论依据。
查看英文原文 English abstract
Objective: Ovarian clear cell carcinoma (OCCC) characteristically overexpresses Tissue Factor (TF; F3 ), yet its biological significance and therapeutic implications remain unclear. We aimed to elucidate the impact of TF expression in OCCC and evaluate the antitumor efficacy of the anti-TF antibody-drug conjugate, tisotumab vedotin (TV), in vitro and in vivo models.
Methods: We performed bulk RNA sequencing (RNA-seq) of 112 clinical OCCC cases to identify transcriptomic features of F3 -high tumors. We then applied single-nucleus RNA-seq (snRNA-seq) to three F3 -high and three F3 -low cases to characterize tumor biology at the single-cell level. Based on these transcriptomic results, we focused on immune-related pathways and immune-checkpoint molecules, with emphasis on VTCN1 (B7-H4). Immunohistochemistry for TF and B7-H4 was performed on 57 OCCC specimens. Finally, we assessed TV activity in patient-derived OCCC spheroids and xenografts.
Results: F3 -high tumors exhibited lower immune scores with upregulation of MYC and cell cycle pathways, and suppression of inflammatory and immune pathways in bulk RNA-seq. Consistently, snRNA-seq showed similar trends in cancer cells, and immune fractions were significantly reduced in F3 -high tumors, indicating an immunologically “cold” state. Notably, the immune-checkpoint molecule VTCN1 was highly expressed in F3 -high tumors and positively correlated with F3 expression. Immunohistochemistry confirmed that B7-H4 was significantly overexpressed in TF-positive tumors, showing a positive correlation between TF and B7-H4 expression.TV activity correlated with TF abundance in vitro and induced marked growth inhibition in F3 -high xenografts; residual tumors showed decreased TF and B7-H4 expression.
Conclusions: TF-high OCCC shows a distinct gene expression pattern, particularly an immunologically cold subtype with B7-H4-mediated immune evasion. TV demonstrates TF-dependent activity, supporting TF as a therapeutic target, and providing rationale for TV-based monotherapy or combinations with immunotherapy in OCCC.
利益披露 Disclosure
Y. Mori, None..
R. Tamura, None..
K. Takahashi, None.
K. Yoshihara,
Genmab US, Inc. ).