Lan Hongwei, Liu Hui, Hou Helei, Zhang Chuantao, Zhu Jingjuan, Zhou Na, Zhang Xiaochun
Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Department of Clinical Laboratory, Qingdao Women's and Children's Hospital, Qingdao, Shandong, China.
Front Immunol. 2025 Apr 7;16:1539616. doi: 10.3389/fimmu.2025.1539616. eCollection 2025.
High-grade serous ovarian cancer (HGSOC) poses significant treatment challenges due to frequent recurrence and resistance to conventional therapies. Combination of anlotinib with immunotherapy have showed promise in various cancers, but its impact on HGSOC remains to be fully elucidated.
A retrospective analysis was performed on 36 HGSOC patients treated with anlotinib-based therapies, including both monotherapy and combination treatment with anti-PD-L1/anti-PD-1 antibody (aPD-L1/aPD-1). Peripheral blood mononuclear cell-derived patient-derived xenograft (PBMC-PDX) model was established from drug-resistant recurrent HGSOC patient-derived tumor cells, and single-cell RNA sequencing (scRNA-seq) was conducted to dissect the TME following treatment with anlotinib, anlotinib + aPD-L1 and anlotinib + aPD-1.
Clinical analysis revealed a disease control rate (DCR) of 71.43% for anlotinib monotherapy, which improved to 100% when combined with aPD-L1/aPD-1. In PBMC-PDX models, treatment evaluation showed that anlotinib decreased tumor volume, an effect further enhanced by its combination with aPD-L1. scRNA-seq analysis demonstrated that anlotinib reduced the proportions of myofibroblastic cancer-associated fibroblasts and ESM1 endothelial cells, resulting in decreased angiogenesis. The combination of anlotinib and aPD-L1 further amplified these effects, promoting CD8 T cell infiltration and reversing T cell exhaustion, whereas anlotinib + aPD-1 showed limited efficacy in this regard. Additionally, anlotinib + immunotherapy induced a shift toward M1 polarization of myeloid cells, enhanced anti-tumor activity, and inhibited immune escape. Cell-cell communication analysis revealed reduced APP-CD74 signaling and increased CD99-CD99 signaling, which might contribute to immune activation.
The combination of anlotinib and aPD-L1 effectively modulates the HGSOC tumor microenvironment by inhibiting angiogenesis, enhancing immune infiltration, and reversing T cell exhaustion.
高级别浆液性卵巢癌（HGSOC）由于频繁复发和对传统疗法耐药，带来了重大的治疗挑战。安罗替尼与免疫疗法联合在多种癌症中显示出前景，但其对HGSOC的影响仍有待充分阐明。
对36例接受基于安罗替尼治疗的HGSOC患者进行回顾性分析，包括单药治疗以及与抗PD-L1/抗PD-1抗体（aPD-L1/aPD-1）联合治疗。从耐药复发的HGSOC患者来源的肿瘤细胞建立外周血单个核细胞衍生的患者来源异种移植（PBMC-PDX）模型，并用安罗替尼、安罗替尼+aPD-L1和安罗替尼+aPD-1治疗后进行单细胞RNA测序（scRNA-seq）以剖析肿瘤微环境。
临床分析显示安罗替尼单药治疗的疾病控制率（DCR）为71.43%，与aPD-L1/aPD-1联合时提高到100%。在PBMC-PDX模型中，治疗评估表明安罗替尼可减小肿瘤体积，与aPD-L1联合时效果进一步增强。scRNA-seq分析表明安罗替尼降低了肌成纤维细胞癌相关成纤维细胞和ESM1内皮细胞的比例，导致血管生成减少。安罗替尼与aPD-L1联合进一步放大了这些作用，促进CD8 T细胞浸润并逆转T细胞耗竭，而安罗替尼+aPD-1在这方面疗效有限。此外，安罗替尼+免疫疗法诱导髓样细胞向M1极化转变，增强抗肿瘤活性并抑制免疫逃逸。细胞间通讯分析显示APP-CD74信号减少而CD99-CD99信号增加，这可能有助于免疫激活。
安罗替尼与aPD-L1联合通过抑制血管生成、增强免疫浸润和逆转T细胞耗竭，有效调节HGSOC肿瘤微环境。
