Circadian pattern subtyping unveiling distinct immune landscapes in breast cancer patients for better immunotherapy
Circadian pattern subtyping unveiling distinct immune landscapes in breast cancer patients for better immunotherapy
复制标题
DOI：
10.1007/s00262-023-03495-3
复制
发表时间：
2023-07
期刊：
影响因子：
--
通讯作者：
Siqi Xiong;Wenqiang Zhu;Liqing Wu;Tianmin Zhou;Wu Wang;Ouyang Zhang;Xiaoliang Xiong;Zhuoqi Liu;Daya Luo
中科院分区：
文献类型：
--
作者：
Siqi Xiong;Wenqiang Zhu;Liqing Wu;Tianmin Zhou;Wu Wang;Ouyang Zhang;Xiaoliang Xiong;Zhuoqi Liu;Daya Luo
背景虽然流行病学研究已经建立了昼夜节律紊乱和肿瘤发生之间的紧密联系，但其作用和机制尚未完全了解，这使得与昼夜节律（CR）相关的治疗靶点的设计变得复杂。在这里，我们的目的是探讨CR的肿瘤间异质性，并阐明其对肿瘤微环境（TME），药物敏感性，和immunotherapy.MethodsBased上的无监督聚类的28 CR基因，两个不同的CR亚型（簇-A和簇-B）在TCGA队列中被确定。我们进一步构建了一个昼夜节律签名（CRS）的基础上，CR基因主要负责聚类量化CR活动和区分CR亚型的个别患者从外部数据集。CR亚型进行了评估TME的特点，功能注释，临床特点，和therapeutic responsibility.ResultsThe集群B（低CRS）组的特点是高度富集的免疫相关通路，高免疫细胞浸润，高抗肿瘤免疫，而集群A（高CRS）组与免疫抑制，突触传递途径，EMT激活，预后不良，耐药。免疫组化（IHC）结果表明，高CD 8 +T细胞浸润与低CR蛋白表达相关。重要的是，低CRS的患者更有可能受益于免疫检查点阻断（ICB）治疗，可能是由于其较高的肿瘤突变负荷（TMB），增加免疫检查点表达，以及较高比例的“热”immunotype.ConclusionIn一个简单的，在CR串扰可以反映乳腺癌的TME免疫反应性。除了提供乳腺癌CR的第一个全面的路径水平分析外，这项工作还强调了CR在免疫治疗中的潜在临床用途。
BackgroundWhile epidemiological studies have established a firm link between circadian disruption and tumorigenesis, the role and mechanism are not fully understood, complicating the design of therapeutic targets related to circadian rhythms (CR). Here, we aimed to explore the intertumoral heterogeneity of CR and elucidate its impact on the tumor microenvironment (TME), drug sensitivity, and immunotherapy.MethodsBased on unsupervised clustering of 28 CR genes, two distinct CR subtypes (cluster-A and cluster-B) were identified in the TCGA cohort. We further constructed a circadian rhythm signature (CRS) based on the CR genes primarily responsible for clustering to quantify CR activity and to distinguish CR subtypes of individual patients from external datasets. CR subtypes were evaluated by TME characteristics, functional annotation, clinical features, and therapeutic response.ResultsThe cluster-B (low-CRS) group was characterized by highly enriched immune-related pathways, high immune cell infiltration, and high anti-tumor immunity, while the cluster-A (high-CRS) group was associated with immunosuppression, synaptic transmission pathways, EMT activation, poor prognosis, and drug resistance. Immunohistochemistry (IHC) results demonstrated that high CD8+T cell infiltration was associated with low-CR-protein expression. Importantly, patients with low CRS were more likely to benefit from immune checkpoint blockade (ICB) treatment, possibly due to their higher tumor mutation burden (TMB), increased immune checkpoint expression, and higher proportion of “hot” immunophenotype.ConclusionIn a nutshell, the cross talk in CR could reflect the TME immunoreactivity in breast cancer. Besides providing the first comprehensive pathway-level analysis of CR in breast cancer, this work highlights the potential clinical utility of CR for immunotherapy.