菊苣酸与PD-1/PD-L1阻断剂联合治疗可改善患者来源的卵巢癌异种移植模型中的免疫治疗反应。

Combination therapy with Chicoric acid and PD-1/PD-L1 blockade improves the immunotherapy response in patient-derived ovarian cancer xenograft model.

作者信息

Lan Hongwei, Zhu Jingjuan, Hou Helei, Zhang Chuantao, Huo Xingfa, Zhang Yuming, Yang Fangfang, Zhou Na, Zhang Xiaochun

机构信息

Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 56 Haier Road, Qingdao, 266000, Shandong, China.

Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China.

出版信息

Cell Commun Signal. 2025 Mar 14;23(1):137. doi: 10.1186/s12964-025-02146-7.

DOI:10.1186/s12964-025-02146-7

PMID:40087780

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11909847/

Abstract

PURPOSE

Limited treatment options exist for refractory ovarian cancer (OC) due to its poor response to immune therapies. Therefore, there is an urgent need to develop new effective treatment strategies. Chicoric acid (CA) is reported to have immune-enhancing properties, but its efficacy in cancer treatment is not well understood. We hypothesize that CA might improve the efficacy of PD-1/PD-L1 blockade immunotherapy in refractory OC patients.

METHODS

Patient-derived xenograft (PDX) models were constructed from chemoresistant advanced high-grade serous ovarian cancer patients. These models were treated with CA, aPD-1/aPD-L1 antibodies, or a combination of both. Single-cell RNA sequencing was performed to analyze the cellular composition of the tumor microenvironment (TME), evaluate treatment efficacy, and explore therapeutic mechanisms. Variations in peripheral blood lymphocytes were analyzed via fluorescence-activated cell sorting. Immunohistochemistry confirmed the variations in tumor-infiltrating lymphocytes and tumor cells.

RESULTS

Immunocompetent peripheral blood mononuclear cell (PBMC)-PDX models were successfully constructed using malignant ascites fluid and PBMCs. After treatment, 158,734 cells from 15 samples were categorized into epithelial cells, T lymphocytes, myeloid cells, fibroblasts, and endothelial cells. CA enhanced the antitumor ability of immune cells against OC cells. Notably, CA stimulated the proliferation of CD45 + and CD3 + cells and promoted the migration of CD8 + and CD4 + T cells from peripheral blood to infiltrate the TME. Additionally, CA enhanced the response of OCs to aPD-L1/aPD-1 treatment, strengthened the interaction between tumor and nontumor cells, and identified APP/CD74 as a critical ligand‒receptor pair. CHI3L1 was also found to be a potential marker for predicting immunotherapy efficacy in OC.

CONCLUSION

This study demonstrated that combination therapy with CA and aPD-1/aPD-L1 might be a promising strategy for treating OC effectively.

摘要

目的

难治性卵巢癌（OC）对免疫疗法反应不佳，治疗选择有限。因此，迫切需要开发新的有效治疗策略。据报道，菊苣酸（CA）具有免疫增强特性，但其在癌症治疗中的疗效尚不清楚。我们假设CA可能会提高难治性OC患者中PD-1/PD-L1阻断免疫疗法的疗效。

方法

从化疗耐药的晚期高级别浆液性卵巢癌患者构建患者来源的异种移植（PDX）模型。这些模型分别用CA、抗PD-1/抗PD-L1抗体或两者联合进行治疗。进行单细胞RNA测序以分析肿瘤微环境（TME）的细胞组成，评估治疗效果，并探索治疗机制。通过荧光激活细胞分选分析外周血淋巴细胞的变化。免疫组织化学证实肿瘤浸润淋巴细胞和肿瘤细胞的变化。

结果

使用恶性腹水和外周血单个核细胞（PBMC）成功构建了具有免疫活性的PBMC-PDX模型。治疗后，来自15个样本的158,734个细胞被分类为上皮细胞、T淋巴细胞、髓样细胞、成纤维细胞和内皮细胞。CA增强了免疫细胞对OC细胞的抗肿瘤能力。值得注意的是，CA刺激CD45+和CD3+细胞的增殖，并促进CD8+和CD4+T细胞从外周血迁移以浸润TME。此外，CA增强了OC对抗PD-L1/抗PD-1治疗的反应，加强了肿瘤细胞与非肿瘤细胞之间的相互作用，并确定APP/CD74为关键的配体-受体对。还发现CHI3L1是预测OC免疫治疗疗效的潜在标志物。