背景:炎症在肿瘤发展中起关键作用。炎症细胞浸润和炎症介质合成导致几种癌症中肿瘤微环境(TME)的变化,尤其是在肝内胆管细胞癌(ICC)。然而,使用可靠的生物标志物确定患者炎症状态的方法仍在探索中。
方法:我们从已发表的研究中检索了244例ICC患者的RNA测序和体细胞突变分析结果以及临床特征。我们进行了一致聚类以鉴定与炎症相关的分子亚型。我们比较了预后模式,临床特征,体细胞突变谱,和炎症亚型的免疫细胞浸润模式。我们进行了定量实时聚合酶链反应(qRT-PCR)和免疫组织化学(IHC)以确认基因表达。我们进行了逻辑回归分析,以构建预测ICC患者炎症状态的列线图。
结果:我们的结果证实ICC可以分为炎症高亚型(IHS)和炎症低亚型(ILS)。每个组的患者都有不同的预后,临床特征,和TME组成。IHS组的ICC患者由于免疫抑制微环境以及KRAS和TP53突变的频率高,预后较差。癌相关成纤维细胞(CAF)衍生的COLEC11减少髓样炎症细胞浸润并减弱炎症反应。qRT-PCR和IHC实验的结果证实,与癌旁组织相比,COLEC11在肿瘤组织中的表达水平显着降低。IHS组的ICC患者更有可能对免疫检查点抑制剂(ICIs)治疗产生反应,因为他们的肿瘤突变负担(TMB)评分较高。肿瘤新抗原负荷(TNB)评分,新抗原计数,和免疫检查点表达水平。最后,我们根据ICC患者的临床特征和炎症基因表达水平,建立了一个有效预测ICC患者炎症状态的列线图.我们评估了校准结果,潜在的歧视,和列线图的临床实用性。
结论:IHS的炎症反应主要由髓系细胞诱导。COLEC11可以降低这组细胞的浸润水平,髓样炎症细胞可能是ICC治疗的新靶点。我们开发了一种新的列线图,可以有效地预测ICC患者的炎症状态,这将有助于指导个性化治疗计划。
BACKGROUND: Inflammation plays a critical role in tumor development. Inflammatory cell infiltration and inflammatory mediator synthesis cause changes in the tumor microenvironment (
TME) in several cancers, especially in intrahepatic cholangiocellular carcinoma (ICC). However, methods to ascertain the inflammatory state of patients using reliable biomarkers are still being explored.
METHODS: We retrieved the RNA sequencing and somatic mutation analyses results and the clinical characteristics of 244 patients with ICC from published studies. We performed consensus clustering to identify the molecular subtypes associated with inflammation. We compared the prognostic patterns, clinical characteristics, somatic mutation profiles, and immune cell infiltration patterns across inflammatory subtypes. We performed quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) to confirm gene expression. We performed logistic regression analyses to construct a nomogram predicting the inflammatory status of patients with ICC.
RESULTS: Our results confirmed that ICC can be categorized into an inflammation-high subtype (IHS) and an inflammation-low subtype (ILS). Patients from each group had distinct prognosis, clinical characteristics, and
TME composition. Patients with ICC in the IHS group showed poorer prognosis owing to the immunosuppressive microenvironment and high frequency of KRAS and TP53 mutations. Cancer-associated fibroblast (CAF)-derived COLEC11 reduced myeloid inflammatory cell infiltration and attenuated inflammatory responses. The results of qRT-PCR and IHC experiments confirmed that COLEC11 expression levels were significantly reduced in tumor tissues compared to those in paracancerous tissues. Patients with ICC in the IHS group were more likely to respond to treatment with immune checkpoint inhibitors (ICIs) owing to their higher tumor mutational burden (TMB) scores, tumor neoantigen burden (TNB) scores, neoantigen counts, and immune checkpoint expression levels. Finally, we developed a nomogram to effectively predict the inflammatory status of patients with ICC based on their clinical characteristics and inflammatory gene expression levels. We evaluated the calibration, discrimination potential, and clinical utility of the nomogram.
CONCLUSIONS: The inflammatory response in IHS is primarily induced by myeloid cells. COLEC11 can reduce the infiltration level of this group of cells, and myeloid inflammatory cells may be a novel target for ICC treatment. We developed a novel nomogram that could effectively predict the inflammatory state of patients with ICC, which will be useful for guiding individualized treatment plans.