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