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NeoPembrOv 试验的免疫组学纵向分析鉴定了高级卵巢癌免疫抵抗的驱动因素。

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

机构信息

"Cancer Immune Surveillance and Therapeutic Targeting" Laboratory, Cancer Research Center of Lyon, INSERM 1052-CNRS 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, 69008, Lyon, France.

Lyon University, Université Claude Bernard Lyon 1, Centre Léon Bérard, 69008, Lyon, France.

出版信息

Nat Commun. 2024 Jul 16;15(1):5932. doi: 10.1038/s41467-024-47000-5.


DOI:10.1038/s41467-024-47000-5
PMID:39013886
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11252308/
Abstract

PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8PD-1 T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high CD8B/FOXP3 and high CD8B/ENTPD1 ratios are significantly associated with positive response to NACT + P, while KDR and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2 endothelial cells, could overcome immune resistance of ovarian cancers.

摘要

PD-1/PD-L1 阻断疗法迄今为止对高级别卵巢癌的生存获益有限。通过使用 NeoPembrOv 随机 II 期试验(NCT03275506)的配对样本,该试验已公布主要结果,并结合 RNA-seq 和多重免疫荧光染色,我们探讨了 NeoAdjuvant ChemoTherapy(NACT)± Pembrolizumab(P)对肿瘤微环境的影响,并确定了与免疫治疗反应相关的参数,这是一项预先计划的探索性分析。事实上,i)联合治疗导致上皮内 CD8PD-1 T 细胞显著增加,ii)将内皮和单核细胞基因特征与 CD8B/FOXP3 表达比值相结合,可预测 NACT+P 的反应,曲线下面积为 0.93(95%CI 0.85-1.00),iii)高 CD8B/FOXP3 和高 CD8B/ENTPD1 比值与 NACT+P 的阳性反应显著相关,而 KDR 和 VEGFR2 表达与耐药性相关。这些结果表明,靶向调节性 T 细胞和内皮细胞,特别是 VEGFR2 内皮细胞,可能克服卵巢癌的免疫抵抗。

相似文献

[1]
Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

Nat Commun. 2024-7-16

[2]
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[3]
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[4]
Spatial Profiling of Ovarian Carcinoma and Tumor Microenvironment Evolution under Neoadjuvant Chemotherapy.

Clin Cancer Res. 2024-7-1

[5]
Sanguisorbae Radix Suppresses Colorectal Tumor Growth Through PD-1/PD-L1 Blockade and Synergistic Effect With Pembrolizumab in a Humanized PD-L1-Expressing Colorectal Cancer Mouse Model.

Front Immunol. 2021

[6]
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Lancet Oncol. 2018-8-14

[7]
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[8]
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J Ovarian Res. 2018-5-30

[9]
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Int J Mol Sci. 2024-6-27

[10]
Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement.

Clin Cancer Res. 2018-1-19

引用本文的文献

[1]
Revisiting Genomic Instability, Tumor Microenvironment and Immune Response in High-Grade Serous Ovarian Cancer.

Geburtshilfe Frauenheilkd. 2025-6-11

[2]
Tumor-stroma proportion on primary tumor as a prognostic biomarker in advanced ovarian cancer patients receiving chemo-immunotherapy as first-line therapy: analyses from the NeoPembrOV/GINECO phase II randomized trial.

ESMO Open. 2025-6

[3]
Risk factors for immunoresistance in advanced non-small cell lung cancer and the advantages of targeted therapy in improving prognosis.

Am J Cancer Res. 2025-2-15

[4]
Composite score of PD-1 CD8 tumor-infiltrating lymphocytes and CD57 CD8 tumor ascites lymphocytes is associated with prognosis and tumor immune microenvironment of patients with advanced high-grade serous ovarian cancer.

Chin J Cancer Res. 2025-1-30

[5]
Immune-molecular interactions in high-grade serous ovarian cancer distinguish long-term survivors.

J Clin Invest. 2024-12-16

[6]
Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial.

Nat Commun. 2024-7-16

本文引用的文献

[1]
Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial.

Nat Commun. 2024-7-16

[2]
Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial.

Clin Cancer Res. 2023-5-1

[3]
The ectonucleotidase CD39 identifies tumor-reactive CD8 T cells predictive of immune checkpoint blockade efficacy in human lung cancer.

Immunity. 2023-1-10

[4]
Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy.

Cancer Cell. 2022-11-14

[5]
Immunologically active phenotype by gene expression profiling is associated with clinical benefit from PD-1/PD-L1 inhibitors in real-world head and neck and lung cancer patients.

Eur J Cancer. 2022-10

[6]
Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models.

PLoS One. 2022

[7]
Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A.

J Clin Oncol. 2022-7-20

[8]
Understanding the impact of chemotherapy on the immune landscape of high-grade serous ovarian cancer.

Gynecol Oncol Rep. 2022-1-7

[9]
SMARCD1 negatively regulates myeloid differentiation of leukemic cells via epigenetic mechanisms.

Blood Adv. 2022-5-24

[10]
Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression.

Sci Adv. 2021-11-5

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