Immune inactivation by neuropilin-1 predicts clinical outcome and therapeutic benefit in muscle-invasive bladder cancer.
Immune inactivation by neuropilin-1 predicts clinical outcome and therapeutic benefit in muscle-invasive bladder cancer.
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Neuropilin-1 引起的免疫失活可预测肌层浸润性膀胱癌的临床结果和治疗效果。
DOI：
10.1007/s00262-022-03153-0
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Wang Zewei
中科院分区：
文献类型：
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作者：
Yu Yanze;Zeng Han;Jin Kaifeng;You Runze;Liu Zhaopei;Zhang Hongyi;Liu Chunnan;Su Xiaohe;Yan Sen;Chang Yuan;Liu Li;Xu Le;Xu Jiejie;Zhu Yu;Wang Zewei
免疫检查点阻断(ICB)和辅助化疗(ACT)已在肌肉浸润性膀胱癌(MIBC)中显示出临床益处，但迄今只发现了几个预测生物标志物。Nrp1已被确定为一个关键的免疫检查点和一个新的免疫治疗靶点，但Nrp1在MIBC中的临床意义尚不清楚。方法本研究涉及三个独立的队列： 210队列(n= 348)、肿瘤基因组图谱队列(TCGA，n=ZSHS，391)和中山医院队列( ，n=ZSHS，n=ZSHS，130)。在接受抗PD-L1药物治疗和辅助化疗(ACT)的患者中，并行检测和验证基于Nrp1表达的风险分层。结果在MIBC中，Nrp1表达的患者存活率较低，对PD-L1阻断和基于顺铂的ACT的预测疗效也较差。进一步研究发现，在MIBC患者中，高水平的Nrp1与耗尽的CD8+T细胞、未成熟的NK细胞和M2极化的肿瘤相关巨噬细胞的浸润密切相关。此外，Nrp1表达升高还与低突变负担和细胞周期通路突变减少相关。结论本研究首次明确并验证了Nrp1表达对MIBC预后和系统治疗反应(PD-L1阻断和ACT)的临床意义。Nrp1的表达与免疫抑制微环境和效应免疫细胞功能障碍有关。对其在MIBC治疗前景中的作用的前瞻性研究值得更多的考虑。
BackgroundImmune checkpoint blockade (ICB) and adjuvant chemotherapy (ACT) have shown clinical benefit in muscle-invasive bladder cancer (MIBC) with only a few predictive biomarkers identified so far. Neuropilin-1 (NRP1) has been identified as a key immune checkpoint and a novel immunotherapeutic target but the clinical significance of NRP1 remains unclear in MIBC.MethodsThree independent cohorts were involved in our study: IMvigor210 Cohort (n= 348), The Cancer Genome Atlas Cohort (TCGA,n= 391), and Zhongshan Hospital Cohort (ZSHS,n= 130). Parallel detection and validation of risk stratification based on NRP1 expression were executed in patients treated with anti-PD-L1 agent and adjuvant chemotherapy (ACT).ResultsNRP1 expression conferred poor survival and predicted response to both PD-L1 blockade and cisplatin-based ACT in MIBC. Further exploration revealed high-level NRP1 was extremely associated with infiltration of exhausted CD8+T cells, immature NK cells and M2 polarized tumor-associated macrophages in MIBC patients. Moreover, elevated NRP1 expression was also correlated with low mutation burden and reduced mutation in cell cycle pathway.ConclusionsOur study firstly identified and validated the clinical implications of NRP1 expression for prognosis and systematic therapeutic responses (PD-L1 blockade and ACT) in MIBC. NRP1 expression was associated with an immunosuppressive microenvironment with dysfunctional effector immune cells. Prospective investigations of its roles in the therapeutic landscape of MIBC warrant more consideration.