鉴定胰腺癌中的免疫细胞浸润图谱以辅助免疫治疗。

Identification of the immune cell infiltration landscape in pancreatic cancer to assist immunotherapy.

机构信息

Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Institute of Hepatobiliary Surgery of Chinese PLA, & Key Laboratory of Digital Hepetobiliary Surgery, PLA, Beijing, China.

Medical School of Chinese PLA, Beijing, China.

出版信息

Future Oncol. 2021 Nov;17(31):4131-4143. doi: 10.2217/fon-2021-0495. Epub 2021 Aug 4.

Abstract

A malignant tumor's immune environment, including infiltrating immune cell status, can be critical to patient outcomes. Recent studies have shown that immune cell infiltration (ICI) in pancreatic cancer (PC) is highly correlated with the response to immunotherapy and patient prognosis. Therefore, we aimed to create an ICI score that accurately predicts patient outcomes and immunotherapeutic efficacy. The ICI statuses of patients with PC were estimated from the publicly available The Cancer Genome Atlas (TCGA) pancreatic ductal adenocarcinoma and GSE57495 gene expression datasets using two computational algorithms (CIBERSORT and ESTIMATE). ICI and transcriptome subsets were defined using a clustering algorithm, and survival analysis was also performed. Principal component analysis was used to calculate the novel ICI score, and gene set enrichment analysis was performed to identify the pathways underlying the defined clusters. The tumor mutational burden (TMB) was further explored in TCGA cohort, and survival analysis was used to assess the capability of the ICI and TMB scores to predict overall survival. Additionally, common driver gene mutations and their differential expression in the different ICI score group were investigated. The ICI landscapes of 240 patients were generated using the devised algorithm, revealing three ICI and three gene clusters whose use improved the prediction of overall survival (p = 0.019 and p < 0.001, respectively). Crucial immune checkpoint genes were differentially expressed among these subtypes; the RIG-I-LIKE and NOD-LIKE receptor signaling pathways were enriched in samples with low ICI scores (p < 0.05). We also found that the TMB scores could predict survival outcomes, whereas the ICI scores also could predict prognoses independent of TMB. Notably, ICI scores could effectively predict responses to immunotherapy. , , ,  and remained the most commonly mutated genes in PC; moreover, and mutation rates were significantly different between the two ICI score groups. We developed a novel ICI score that could independently predict the response to immunotherapy and survival of patients with PC. Evaluation of the ICI landscape in a larger cohort could clarify the interactions between these infiltrating cells, the tumor microenvironment and response to immunotherapy.

摘要

恶性肿瘤的免疫环境,包括浸润免疫细胞状态,对患者的预后至关重要。最近的研究表明,胰腺癌(PC)中的免疫细胞浸润(ICI)与免疫治疗反应和患者预后高度相关。因此,我们旨在创建一个能够准确预测患者预后和免疫治疗效果的 ICI 评分。使用两种计算算法(CIBERSORT 和 ESTIMATE),从公开的癌症基因组图谱(TCGA)胰腺导管腺癌和 GSE57495 基因表达数据集估算 PC 患者的 ICI 状态。使用聚类算法定义 ICI 和转录组亚群,并进行生存分析。使用主成分分析计算新的 ICI 评分,并进行基因集富集分析以确定定义的聚类所涉及的途径。进一步在 TCGA 队列中探索肿瘤突变负担(TMB),并进行生存分析以评估 ICI 和 TMB 评分预测总生存率的能力。此外,还研究了不同 ICI 评分组中常见驱动基因突变及其差异表达。使用设计的算法生成了 240 名患者的 ICI 图谱,揭示了三个 ICI 和三个基因簇,其使用改善了总体生存的预测(p=0.019 和 p<0.001)。这些亚型中差异表达的关键免疫检查点基因;低 ICI 评分样本中富集了 RIG-I-LIKE 和 NOD-LIKE 受体信号通路(p<0.05)。我们还发现 TMB 评分可以预测生存结果,而 ICI 评分也可以独立于 TMB 预测预后。值得注意的是,ICI 评分可以有效地预测免疫治疗的反应。在 PC 中, 、 、 、 和 仍然是最常见的突变基因;此外,两个 ICI 评分组之间的 和 突变率有显著差异。我们开发了一种新的 ICI 评分,可以独立预测 PC 患者对免疫治疗的反应和生存。在更大的队列中评估 ICI 景观可以阐明这些浸润细胞、肿瘤微环境与免疫治疗反应之间的相互作用。

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